Controlled delivery system

ABSTRACT

The present invention relates to novel anesthetic compositions containing a non-polymeric carrier material and an anesthetic, where the compositions are suitable for providing a sustained local anesthesia without an initial burst and having a duration for about 24 hours or longer. Certain compositions are also provided that include a first anesthetic and a second anesthetic. In such compositions, the second anesthetic is a solvent for the first anesthetic and provides an initial anesthetic effect upon administration to a subject. The non-polymeric carrier may optionally be a high viscosity liquid carrier material such as a suitable sugar ester. The compositions can further include one or more additional ingredients including active and inactive materials. Methods of using the compositions of the invention to produce a sustained anesthetic effect at a site in a subject are also provided.

TECHNICAL FIELD

The present invention relates generally to the field of controlleddelivery systems, and more particularly controlled delivery systemscontaining an active agent that is able to provide a localizedanesthetic effect, where the systems are suitable for use in connectionwith surgical and medical treatments, and as medicaments for use in postoperative recovery procedures.

BACKGROUND OF THE INVENTION

Biodegradable controlled delivery systems for active agents are wellknown in the art. Biodegradable carriers for drug delivery are usefulbecause they obviate the need to remove the drug-depleted device.

The most common carrier materials used for controlled delivery systemsare polymers. The field of biodegradable polymers has developed rapidlysince the synthesis and biodegradability of polylactic acid was reportedby Kulkami et al. (1966) Arch. Surg. 93:839. Examples of other polymerswhich have been reported as useful as a matrix material for controlleddelivery systems include polyanhydrides, polyesters such aspolyglycolides and polylactide-co-glycolides, polyamino acids such aspolylysine, polymers and copolymers of polyethylene oxide, acrylicterminated polyethylene oxide, polyamides, polyurethanes,polyorthoesters, polyacrylonitriles, and polyphosphazenes. See, e.g.,U.S. Pat. Nos. 4,891,225 and 4,906,474 (polyanhydrides); U.S. Pat. No.4,767,628 (polylactide, polylactide-co-glycolide acid); U.S. Pat. No.4,530,840 (polylactide, polyglycolide, and copolymers); and U.S. Pat.No. 5,234,520 (biodegradable polymers for controlled delivery intreating periodontal disease).

Degradable materials of biological origin are well known including, forexample, crosslinked gelatin. Hyaluronic acid has been crosslinked andused as a degradable swelling polymer for biomedical applications (see,e.g., U.S. Pat. No. 4,957,744 and Della Valle et al. (1991) Polym.Mater. Sci. Eng., 62:731-735).

Biodegradable hydrogels have also been developed for use in controlleddelivery systems and serve as carriers of biologically active materialssuch as hormones, enzymes, antibiotics, antineoplastic agents, and cellsuspensions. See, e.g., U.S. Pat. No. 5,149,543.

Hydrogel compositions are also commonly used as substrates for cell andtissue culture, impression materials for prosthetics, wound-packingmaterials, or as solid phase materials in size exclusion or affinitychromatography applications. For example, nonporous, deformed and/orderivatized agarose hydrogel compositions have been used inhigh-performance liquid chromatography and affinity chromatographymethods (Li et al. (1990) Preparative Biochem. 20:107-121), andsuperporous agarose hydrogel beads have been used as a support inhydrophobic interaction chromatography (Gustavsson et al. (1999) J.Chromatography 830:275-284).

Many dispersion systems are also currently in use as carriers ofsubstances, particularly biologically active compounds. Dispersionsystems used for pharmaceutical and cosmetic formulations can becategorized as either suspensions or emulsions. Suspensions arecomprised of solid particles ranging in size from a few nanometers up tohundreds of microns, dispersed in a liquid medium using suspendingagents. Solid particles include microspheres, microcapsules, andnanospheres. Emulsions are generally dispersions of one liquid inanother stabilized by an interfacial film of emulsifiers such assurfactants and lipids. Emulsion formulations include water in oil andoil in water emulsions, multiple emulsions, microemulsions,microdroplets, and liposomes. Microdroplets are unilamellar phospholipidvesicles that consist of a spherical lipid layer with an oil phaseinside, for example, those described in U.S. Pat. Nos. 4,622,219 and4,725,442. Liposomes are phospholipid vesicles prepared by mixingwater-insoluble polar lipids with an aqueous solution. The unfavorableentropy caused by mixing the insoluble lipid in the water produces ahighly ordered assembly of concentric closed membranes of phospholipidwith entrapped aqueous solution.

A number of systems for forming an implant in situ have been described.For example, U.S. Pat. No. 4,938,763 describes a method for forming animplant by dissolving a non-reactive, water insoluble thermoplasticpolymer in a biocompatible, water-soluble solvent to form a liquid,placing the liquid within the body, and allowing the solvent todissipate to produce a solid implant. The polymer solution can be placedin the body via syringe. The implant can assume the shape of itssurrounding cavity. Alternatively, an implant can be formed fromreactive, liquid oligomeric polymers which contain no solvent and whichcure in place to form solids, usually with the addition of a curingcatalyst.

A number of polymeric controlled delivery systems for the delivery oflocal anesthetics have been described in the art. Although suchpolymeric delivery systems may provide suitable controlled releaseproperties for the anesthetic and further overcome disadvantagesassociated with injection of neat anesthetics (e.g., dispersion awayfrom the target site, entry into blood stream, and systemic toxicities),it is difficult to overcome certain disadvantages associated with thepolymeric systems, such as failure to avoid systemic initial burstrelease of the anesthetic or having to provide enhancer agents in orderto overcome too little release of the anesthetic from the systems.

SUMMARY OF THE INVENTION

Non-polymeric controlled delivery carrier systems for administration ofan anesthetic agent of interest are provided. It is thus an object ofthe present invention to provide a long-acting controlled deliverysystem that releases an anesthetic over a prolonged period of time,sufficient to provide a local anesthetic effect at a site ofadministration for at least about 24 hours after administration,preferably at least about 36 to 48 hours after administration, and morepreferably at least about 48 to 72 hours after administration. It isalso an object of the present invention that release of the activeanesthetic agent from the long-acting anesthetic composition occurswithout an initial burst.

It is more particularly an object of the present invention to provide acomposition containing an anesthetic and a pharmaceutically acceptablenon-polymeric carrier. The non-polymeric carrier controls release of theanesthetic to provide an anesthetic effect characterized by sustainedlocal anesthesia after administration to a subject without an initialburst and a duration of at least about 24 hours after administration,preferably at least about 36 to 48 hours after administration, and morepreferably at least about 48 to 72 hours after administration.

In one aspect of the invention, the non-polymeric carrier is sufficientto provide either a first order controlled release profile of theanesthetic, or a pseudo-zero order release profile of the anesthetic. Incertain embodiments, the anesthetic is a local anesthetic, for examplean amide- or ester-type local anesthetic. In a preferred embodiment, theanesthetic is bupivacaine that may further be provided in free baseform. In other embodiments, the composition is capable of providing asustained mean steady state plasma concentration (C_(ss)) of theanesthetic of at least about 200 ng/mL for a period of at least about 24hours when the composition is administered subcutaneously, preferably atleast about 250 ng/mL, or at least about 300 ng/mL, or at least about350 ng/mL.

In another aspect of the invention, the non-polymeric carrier issubstantially insoluble in water or in an aqueous biological system. Insuch compositions, the pharmaceutical may further contain a solvent thatis dispersible, soluble or miscible in water or in an aqueous system.The solvent may thus be an organic solvent that is capable ofdissipating, diffusing or leaching away from the composition uponplacement within a biological system, whereby the carrier can thencoagulate or precipitate to form a solid implant in situ.

In yet another aspect of the invention, the non-polymeric carrier is aliquid, preferably a high viscosity liquid carrier material (“HVLCM”)having a viscosity of at least about 5,000 cP at 37° C. and which doesnot crystallize neat under ambient or physiological conditions. Suchliquid carrier materials can be combined with a solvent in which thecarrier material is soluble. If a HVLCM is used, it is preferred thatthe solvent is sufficient to lower the viscosity of the HVLCM. Incertain embodiments, the solvent may be a second anesthetic agent suchas benzyl alcohol. The compositions may be provided in any suitableform, for example, as an emulsion, a paste, a gel, a slurry, a cream, afilm, a spray, a solid, a particle, a microparticle, a powder, animplant, or a liquid. In certain embodiments, the composition furtherincludes a material that is immiscible with the non-polymeric carrier,for example where the composition is an emulsion. In these compositions,the carrier may be present in either the dispersed or the continuousphase of the emulsion.

It is also an object of the present invention to provide a compositioncontaining an anesthetic and a pharmaceutically acceptable non-polymericcarrier. The non-polymeric carrier controls release of the anesthetic toprovide an anesthetic effect characterized by sustained local anesthesiaafter administration to a subject, where the composition is furthercapable of providing a sustained mean steady state plasma concentration(C_(ss)) of the anesthetic of at least about 200 ng/mL for a period ofat least about 24 hours when the composition is administeredsubcutaneously, preferably at least about 250 ng/mL, or at least about300 ng/mL, or at least about 350 ng/mL.

In one aspect of the invention, the composition is capable of providinga sustained mean steady state plasma concentration (C_(ss)) for a periodof at least about 48 hours. In another aspect, the composition isfurther characterized as not having any substantial initial burst. Instill other aspects, the non-polymeric carrier is sufficient to provideeither a first order controlled release profile of the anesthetic, or apseudo-zero order release profile of the anesthetic. In certainembodiments, the anesthetic is a local anesthetic, for example an amide-or ester-type local anesthetic. In a preferred embodiment, theanesthetic is bupivacaine that may further be provided in free baseform.

In another aspect of the invention, the non-polymeric carrier issubstantially insoluble in water or in an aqueous biological system. Insuch compositions, the pharmaceutical may further contain a solvent thatis dispersible, soluble or miscible in water or in an aqueous system.The solvent may thus be an organic solvent that is capable ofdissipating, diffusing or leaching away from the composition uponplacement within a biological system, whereby the carrier can thencoagulate or precipitate to form a solid implant in situ.

In yet another aspect of the invention, the non-polymeric carrier is aliquid, preferably a high viscosity liquid carrier material (“HVLCM”)having a viscosity of at least about 5,000 cP at 37° C. and which doesnot crystallize neat under ambient or physiological conditions. Suchliquid carrier materials can be combined with a solvent in which thecarrier material is soluble. If a HVLCM is used, it is preferred thatthe solvent is sufficient to lower the viscosity of the HVLCM. Incertain embodiments, the solvent may be a second anesthetic agent suchas benzyl alcohol. The compositions may be provided in any suitableform, for example, as an emulsion, a paste, a gel, a slurry, a cream, afilm, a spray, a solid, a particle, a microparticle, a powder, animplant, or a liquid. In certain embodiments, the composition furtherincludes a material that is immiscible with the non-polymeric carrier,for example where the composition is an emulsion. In these compositions,the carrier may be present in either the dispersed or the continuousphase of the emulsion.

It is a related object of the invention to provide a compositioncontaining a first anesthetic, a second anesthetic, and apharmaceutically acceptable non-polymeric carrier. In the composition,the second anesthetic is a solvent for the first anesthetic and providesan initial anesthetic effect upon administration to a subject. Thenon-polymeric carrier controls release of the first anesthetic toprovide a subsequent anesthetic effect characterized by sustained localanesthesia having an onset within about 2 hours of administration to asubject without an initial burst and a duration of at least about 24hours after administration, preferably at least about 36 to 48 hoursafter administration, and more preferably at least about 48 to 72 hoursafter administration.

In one aspect of the invention, the non-polymeric carrier is sufficientto provide either a first order controlled release profile of theanesthetic, or a pseudo-zero order release profile of the anesthetic. Inother embodiments, the composition is capable of providing a sustainedmean steady state plasma concentration (C_(ss)) of the anesthetic of atleast about 200 ng/mL for a period of at least about 24 hours when thecomposition is administered subcutaneously, preferably at least about250 ng/mL, or at least about 300 ng/mL, or at least about 350 ng/mL. Incertain other embodiments, the first anesthetic is a local anesthetic,for example an amide- or ester-type local anesthetic. In still furtherembodiments, the second anesthetic is also a solvent for thenon-polymeric carrier. The second anesthetic may be an alcohol, aromaticalcohol, acid or acid derivative solvent, or any combination of suchsolvents. In a preferred embodiment, the second anesthetic is benzylalcohol. In another preferred embodiment, the first anesthetic isbupivacaine that may further be provided in free base form.

In another aspect of the invention, the non-polymeric carrier issubstantially insoluble in water or in an aqueous biological system. Insuch compositions, the pharmaceutical may further contain a solvent thatis dispersible, soluble or miscible in water or in an aqueous system.The solvent may thus be an organic solvent that is capable ofdissipating, diffusing or leaching away from the composition uponplacement within a biological system, whereby the carrier can thencoagulate or precipitate to form a solid implant in situ.

In yet another aspect of the invention, the non-polymeric carrier is aliquid, preferably a high viscosity liquid carrier material (“HVLCM”)having a viscosity of at least about 5,000 cP at 37° C. and which doesnot crystallize neat under ambient or physiological conditions. Suchliquid carrier materials can be combined with a solvent in which thecarrier material is soluble. If a HVLCM is used, it is preferred thatthe solvent is sufficient to lower the viscosity of the HVLCM. Incertain embodiments, the solvent may be a second anesthetic agent suchas benzyl alcohol. The compositions may be provided in any suitableform, for example, as an emulsion, a paste, a gel, a slurry, a cream, afilm, a spray, a solid, a particle, a microparticle, a powder, animplant, or a liquid. In certain embodiments, the composition furtherincludes a material that is immiscible with the non-polymeric carrier,for example where the composition is an emulsion. In these compositions,the carrier may be present in either the dispersed or the continuousphase of the emulsion.

It is also a related object of the invention to provide a compositioncomprising a non-polymeric, non-water soluble high viscosity liquidcarrier material (“HVLCM”) having a viscosity of at least 5,000 cP at37° C. that does not crystallize neat under ambient or physiologicalconditions, a first anesthetic and a second anesthetic. Here again thesecond anesthetic is a solvent for the first anesthetic and provides aninitial anesthetic effect upon administration to a subject. The HVLCMcontrols release of the first anesthetic to provide a subsequentanesthetic effect characterized by sustained local anesthesia having anonset within about 2 hours of administration to a subject without aninitial burst and a duration of at least about 24 hours afteradministration, preferably at least about 36 to 48 hours afteradministration, and more preferably at least about 48 to 72 hours afteradministration. In certain embodiments, the composition is capable ofproviding a sustained mean steady state plasma concentration (C_(ss)) ofthe anesthetic of at least about 200 ng/mL for a period of at leastabout 24 hours when the composition is administered subcutaneously,preferably at least about 250 ng/mL, or at least about 300 ng/mL, or atleast about 350 ng/mL.

In one aspect of the invention, the first anesthetic is a localanesthetic, for example an amide- or ester-type local anesthetic. Inother embodiments, the second anesthetic is also a solvent for theHVLCM. The second anesthetic may be an alcohol, aromatic alcohol, acidor acid derivative solvent, or any combination of such solvents. In apreferred embodiment, the second anesthetic is benzyl alcohol. Inanother preferred embodiment, the first anesthetic is bupivacaine thatmay further be provided in free base form. In still other preferredembodiments, the HVLCM is an ester, such as a sugar ester like sucroseacetate isobutyrate. In these compositions, it may be useful to providea solvent in which the HVVLCM is soluble.

It is further related object of the invention to provide a compositioncomprising a non-polymeric, non-water soluble high viscosity liquidcarrier material (“HVLCM”) having a viscosity of at least 5,000 cP at37° C. that does not crystallize neat under ambient or physiologicalconditions, a first anesthetic and a second anesthetic. Here again thesecond anesthetic is a solvent for the first anesthetic and provides aninitial anesthetic effect upon administration to a subject. The HVLCMcontrols release of the first anesthetic to provide a subsequentanesthetic effect characterized by sustained local anesthesia, where thecomposition is further capable of providing a sustained mean steadystate plasma concentration (C_(ss)) of the anesthetic of at least about200 ng/mL for a period of at least about 24 hours when the compositionis administered subcutaneously, preferably at least about 250 ng/mL, orat least about 300 ng/mL, or at least about 350 ng/mL.

In one aspect of the invention, the composition is capable of providinga sustained mean steady state plasma concentration (C_(ss)) for a periodof at least about 48 hours. In another aspect, the composition isfurther characterized as not having any substantial initial burst.

In another aspect of the invention, the first anesthetic is a localanesthetic, for example an amide- or ester-type local anesthetic. Inother embodiments, the second anesthetic is also a solvent for theHVLCM. The second anesthetic may be an alcohol, aromatic alcohol, acidor acid derivative solvent, or any combination of such solvents. In apreferred embodiment, the second anesthetic is benzyl alcohol. Inanother preferred embodiment, the first anesthetic is bupivacaine thatmay further be provided in free base form. In still other preferredembodiments, the HVLCM is an ester, such as a sugar ester like sucroseacetate isobutyrate. In these compositions, it may be useful to providea solvent in which the HVVLCM is soluble.

It is a further object of the invention to provide a method forproviding an anesthetic effect at a site in a subject. The methodcomprises administering a composition at, near, in, or adjacent to thesite, where the composition includes an anesthetic and apharmaceutically acceptable non-polymeric carrier. The non-polymericcarrier controls release of the anesthetic to provide an anestheticeffect characterized by sustained local anesthesia after administrationto the subject without an initial burst and having a duration of atleast about 24 hours after administration.

In one aspect of the invention, the anesthetic is a local anesthetic,for example an amide- or ester-type local anesthetic.

It is a related object of the invention to provide a method forproviding an anesthetic effect at a site in a subject. The methodcomprises administering a composition at, near, in, or adjacent to thesite, where the composition includes an anesthetic and apharmaceutically acceptable non-polymeric carrier. The non-polymericcarrier controls release of the anesthetic to provide an anestheticeffect characterized by sustained local anesthesia after administrationto the subject, where the composition is further capable of providing asustained mean steady state plasma concentration (C_(ss)) of theanesthetic of at least about 200 ng/mL for a period of at least about 24hours when the composition is administered subcutaneously.

In one aspect of the invention, the anesthetic is a local anesthetic,for example an amide- or ester-type local anesthetic.

It is a still further object of the invention to provide a method forproviding an anesthetic effect at a site in a subject. The methodcomprises administering a composition at, near, in, or adjacent to thesite, where the composition includes a first anesthetic, a secondanesthetic, and a pharmaceutically acceptable non-polymeric carrier. Thesecond anesthetic is a solvent for the first anesthetic and provides aninitial anesthetic effect at the site upon administration. Thenon-polymeric carrier controls release of the first anesthetic toprovide a subsequent anesthetic effect characterized by sustained localanesthesia at the site having an onset within about 2 hours ofadministration without an initial burst and a duration of at least about24 hours after administration, preferably at least about 36 to 48 hoursafter administration, and more preferably at least about 48 to 72 hoursafter administration.

In one aspect of the invention, the non-polymeric carrier is a liquid,preferably a high viscosity liquid carrier material (“HVLCM”) that isnon-water soluble and has a viscosity of at least about 5,000 cP at 37°C. and further which does not crystallize neat under ambient orphysiological conditions. Such liquid carrier materials can be combinedwith a solvent in which the carrier material is soluble. If a HVLCM isused, it is preferred that the solvent is sufficient to lower theviscosity of the HVLCM. In certain embodiments, the solvent may be asecond anesthetic agent such as benzyl alcohol.

In another aspect of the invention, the first anesthetic is a localanesthetic, for example an amide- or ester-type local anesthetic. Inother embodiments, the second anesthetic is also a solvent for theHVLCM. The second anesthetic may be an alcohol, aromatic alcohol, acidor acid derivative solvent, or any combination of such solvents. In apreferred embodiment, the second anesthetic is benzyl alcohol. Inanother preferred embodiment, the first anesthetic is bupivacaine thatmay further be provided in free base form. In still other preferredembodiments, the HVLCM is an ester, such as a sugar ester like sucroseacetate isobutyrate. In these compositions, it may be useful to providea solvent in which the HVVLCM is soluble.

In yet another aspect of the invention, the composition is administeredby topical administration, transdermal administration, injection or asan implant to the site. In certain embodiments, the composition isadministered to a site that is a surgical wound, and the composition isadministered into and/or adjacent to the wound.

It is a still further object of the invention to provide a method forproviding an anesthetic effect at a site in a subject. The methodcomprises administering a composition at, near, in, or adjacent to thesite, where the composition includes a first anesthetic, a secondanesthetic, and a pharmaceutically acceptable non-polymeric carrier. Thesecond anesthetic is a solvent for the first anesthetic and provides aninitial anesthetic effect at the site upon administration. Thenon-polymeric carrier controls release of the first anesthetic toprovide a subsequent anesthetic effect characterized by sustained localanesthesia at the site, and the composition is further capable ofproviding a sustained mean steady state plasma concentration (C_(ss)) ofthe anesthetic of at least about 200 ng/mL for a period of at leastabout 24 hours when the composition is administered subcutaneously.

In one aspect of the invention, the non-polymeric carrier is a liquid,preferably a high viscosity liquid carrier material (“HVLCM”) that isnon-water soluble and has a viscosity of at least about 5,000 cP at 37°C. and further which does not crystallize neat under ambient orphysiological conditions. Such liquid carrier materials can be combinedwith a solvent in which the carrier material is soluble. If a HVLCM isused, it is preferred that the solvent is sufficient to lower theviscosity of the HVLCM. In certain embodiments, the solvent may be asecond anesthetic agent such as benzyl alcohol.

In another aspect of the invention, the first anesthetic is a localanesthetic, for example an amide- or ester-type local anesthetic. Inother embodiments, the second anesthetic is also a solvent for theHVLCM. The second anesthetic may be an alcohol, aromatic alcohol, acidor acid derivative solvent, or any combination of such solvents. In apreferred embodiment, the second anesthetic is benzyl alcohol. Inanother preferred embodiment, the first anesthetic is bupivacaine thatmay further be provided in free base form. In still other preferredembodiments, the HVLCM is an ester, such as a sugar ester like sucroseacetate isobutyrate. In these compositions, it may be useful to providea solvent in which the HVVLCM is soluble.

In yet another aspect of the invention, the composition is administeredby topical administration, transdermal administration, injection or asan implant to the site. In certain embodiments, the composition isadministered to a site that is a surgical wound, and the composition isadministered into and/or adjacent to the wound.

It is an advantage of the present invention that the non-polymericcarrier material is able to control release of the anesthetic agent toboth avoid an initial burst release and to provide for a sustainedanesthetic effect for at least about 24 hours. It is a further advantageof the invention that the compositions are readily constructed toprovide any number of different pharmaceutical forms, and further toprovide a wide range of different pharmacological releasecharacteristics depending upon the intended site of administration andmedical application.

These and other objects, aspects and advantages of the present inventionwill readily occur to the skilled practitioner upon reading the instantdisclosure and specification.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the mean plasma bupivacaine levels over 7 days (thepharmacodynamic results) from Example 3, wherein the Cohort 1 data isrepresented by the bottom curve, and the Cohort 2 data is represented bythe top curve.

FIG. 2 depicts the mean plasma bupivacaine levels over 0-144 hours (thepharmacodynamic results) from Example 4, Cohort 1.

FIG. 3 depicts the mean plasma bupivacaine levels over 0-12 hours (thepharmacodynamic results) from Example 4, Cohort 1.

FIG. 4 depicts the mean plasma bupivacaine levels over 0-300 hours (thepharmacodynamic results) from Example 4, Cohort 2, where the subgroup 3data is represented by the bottom curve (?), the subgroup 2 data isrepresented by the middle curve (?), and the subgroup 1 data isrepresented by the top curve (?).

FIG. 5 depicts the mean plasma bupivacaine levels over 0-12 hours (thepharmacodynamic results) from Example 4, Cohort 2, where the subgroup 3data is represented by the bottom curve (?), the subgroup 2 data isrepresented by the middle curve (?), and the subgroup 1 data isrepresented by the top curve (?).

FIG. 6 depicts the mean “at rest” incision site pain scores recordedusing a 0 to 100 mm visual analog scale (VAS) from Example 4, Cohort 2,where the subgroup 3 data is represented by the top curve (?), thesubgroup 2 data is represented by the middle curve (?), and the subgroup1 data is represented by the bottom curve (?).

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified carrier materials or process parameters as such may, ofcourse, vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments of theinvention only, and is not intended to be limiting.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to “a non-polymeric carrier” includes a mixture of two or moresuch carriers, reference to “a solvent” includes a mixture of two ormore such carriers, reference to “an anesthetic” includes mixtures oftwo or more such agents, and the like.

It is an object of the present invention to provide a long-actingcontrolled release system that releases an anesthetic over a prolongedperiod of time, sufficient to provide a local anesthetic effect at asite of administration for at least about 24 hours after administration,preferably at least about 36 to 48 hours after administration, and morepreferably at least about 48 to 72 hours after administration. It isalso an object of the present invention that release of the activeanesthetic agent from the long-acting anesthetic composition occurswithout an initial burst. It is a further object of the presentinvention that the composition releases the active anesthetic agent fromthe long-acting anesthetic composition to provide a sustained meansteady state plasma concentration (C_(ss)) of the anesthetic of at leastabout 200 ng/mL for a period of at least about 24 hours when thecomposition is administered subcutaneously, preferably at least about250 ng/mL, or at least about 300 ng/mL, or at least about 350 ng/mL.

It is also an object of the present invention to provide a compositioncontaining an anesthetic and a pharmaceutically acceptable non-polymericcarrier. The non-polymeric carrier controls release of the anesthetic toprovide an anesthetic effect characterized by sustained local anesthesiaafter administration to a subject without an initial burst and aduration of at least about 24 hours after administration, preferably atleast about 36 to 48 hours after administration, and more preferably atleast about 48 to 72 hours after administration.

It is also an object of the present invention to provide a compositioncontaining an anesthetic and a pharmaceutically acceptable non-polymericcarrier. The non-polymeric carrier controls release of the anesthetic toprovide an anesthetic effect characterized by sustained local anesthesiaafter administration to a subject, wherein the composition provides asustained mean steady state plasma concentration (C_(ss)) of theanesthetic of at least about 200 ng/mL for a period of at least about 24hours when the composition is administered subcutaneously, preferably atleast about 250 ng/mL, or at least about 300 ng/mL, or at least about350 ng/mL.

It is a related object of the invention to provide a compositioncontaining a first anesthetic, a second anesthetic, and apharmaceutically acceptable non-polymeric carrier. In the composition,the second anesthetic is a solvent for the first anesthetic and providesan initial anesthetic effect upon administration to a subject. Thenon-polymeric carrier controls release of the first anesthetic toprovide a subsequent anesthetic effect characterized by sustained localanesthesia having an onset within about 2 hours of administration to asubject without an initial burst and a duration of at least about 24hours after administration, preferably at least about 36 to 48 hoursafter administration, and more preferably at least about 48 to 72 hoursafter administration.

It is also a related object of the invention to provide a compositioncomprising a non-polymeric, non-water soluble high viscosity liquidcarrier material (“HVLCM”) having a viscosity of at least 5,000 cP at37° C. that does not crystallize neat under ambient or physiologicalconditions, a first anesthetic and a second anesthetic. Here again thesecond anesthetic is a solvent for the first anesthetic and provides aninitial anesthetic effect upon administration to a subject. The HVLCMcontrols release of the first anesthetic to provide a subsequentanesthetic effect characterized by sustained local anesthesia having anonset within about 2 hours of administration to a subject without aninitial burst and a duration of at least about 24 hours afteradministration, preferably at least about 36 to 48 hours afteradministration, and more preferably at least about 48 to 72 hours afteradministration.

It is a further related object of the invention to provide a compositioncomprising a non-polymeric, non-water soluble high viscosity liquidcarrier material (“HVLCM”) having a viscosity of at least 5,000 cP at37° C. that does not crystallize neat under ambient or physiologicalconditions, a first anesthetic and a second anesthetic. Here again thesecond anesthetic is a solvent for the first anesthetic and provides aninitial anesthetic effect upon administration to a subject. The HVLCMcontrols release of the first anesthetic to provide a subsequentanesthetic effect characterized by sustained local anesthesia, and thecomposition provides a sustained mean steady state plasma concentration(C_(ss)) of the anesthetic of at least about 200 ng/mL for a period ofat least about 24 hours when the composition is administeredsubcutaneously, preferably at least about 250 ng/mL, or at least about300 ng/mL, or at least about 350 ng/mL.

It is a further object of the invention to provide a method forproviding an anesthetic effect at a site in a subject. The methodcomprises administering a composition at, near, in, or adjacent to thesite, where the composition includes an anesthetic and apharmaceutically acceptable non-polymeric carrier. The non-polymericcarrier controls release of the anesthetic to provide an anestheticeffect characterized by sustained local anesthesia after administrationto the subject without an initial burst and having a duration of atleast about 24 hours after administration.

It is yet a further object of the invention to provide a method forproviding an anesthetic effect at a site in a subject. The methodcomprises administering a composition at, near, in, or adjacent to thesite, where the composition includes an anesthetic and apharmaceutically acceptable non-polymeric carrier. The non-polymericcarrier controls release of the anesthetic to provide an anestheticeffect characterized by sustained local anesthesia after administrationto the subject, and the composition provides a sustained mean steadystate plasma concentration (C_(ss)) of the anesthetic of at least about200 ng/mL for a period of at least about 24 hours when the compositionis administered subcutaneously.

It is a still further object of the invention to provide a method forproviding an anesthetic effect at a site in a subject. The methodcomprises administering a composition at, near, in, or adjacent to thesite, where the composition includes a first anesthetic, a secondanesthetic, and a pharmaceutically acceptable non-polymeric carrier. Thesecond anesthetic is a solvent for the first anesthetic and provides aninitial anesthetic effect at the site upon administration. Thenon-polymeric carrier controls release of the first anesthetic toprovide a subsequent anesthetic effect characterized by sustained localanesthesia at the site having an onset within about 2 hours ofadministration without an initial burst and a duration of at least about24 hours after administration, preferably at least about 36 to 48 hoursafter administration, and more preferably at least about 48 to 72 hoursafter administration.

It is also an object of the invention to provide a method for providingan anesthetic effect at a site in a subject. The method comprisesadministering a composition at, near, in, or adjacent to the site, wherethe composition includes a first anesthetic, a second anesthetic, and apharmaceutically acceptable non-polymeric carrier. The second anestheticis a solvent for the first anesthetic and provides an initial anestheticeffect at the site upon administration. The non-polymeric carriercontrols release of the first anesthetic to provide a subsequentanesthetic effect characterized by sustained local anesthesia at thesite, and the composition provides a sustained mean steady state plasmaconcentration (C_(ss)) of the anesthetic of at least about 200 ng/mL fora period of at least about 24 hours when the composition is administeredsubcutaneously.

The phrase “without an initial burst,” as used herein, intends that theparticular agent being referred to does not release from the compositionupon normal administration and become pharmacologically available in anappreciable amount during a predetermined initial period. The presenceand level of an initial burst of an agent from a given composition canbe readily determined by the skilled artisan employing standardpharmacological testing techniques well known in the art. Suitable invitro burst release characterization methods include the USP II PaddleMethod, using standard buffer, mixing and heat conditions. The burstrelease characteristics of a given composition can also readily bedetermined using standard in vivo testing, such as by monitoring plasmaconcentrations of the agent of interest in an animal subject, over agiven time period. In the compositions of the present invention,preferably less than about 40 to 60% of the anesthetic agent is releasedwithin the first 24 hours, more preferably less than about 30 to 50%,and even more preferably less than about 20 to 40% is released withinthis initial time period. In certain other preferred embodiments, lessthan about 5 to 10% of the anesthetic agent is released within the firsthour, more preferably less than about 3 to 7% is released within thisinitial time period.

Accordingly, the compositions of the present invention will contain atleast one anesthetic agent in a controlled release system that releasesan anesthetic over a prolonged period of time. In certain embodiments,the anesthetic is present in the instant compositions in an amount offrom about 95 to about 1 percent by weight relative to the total weightof the composition (wt %), in an amount of from about 30 to 1 wt %, inan amount of from about 25 to 5 wt %, or in an amount of about 20 to 10wt %, depending on the identity of the anesthetic and the intended usethereof.

As used herein, the term “anesthetic” intends any agent that providesreversible local numbness, pain relief, blocks impulse conduction alongnerve axions and other excitable membranes, such as a regional blockageof nociceptive pathways (afferent and/or efferent), analgesia, and/oranesthesia. See, e.g., Strichartz, G. R. (Ed.) Local Anesthetics,Handbook of Experimental Pharmacology, vol. 81, Springer, Berlin/NewYork, (1987). The term also includes any agent which, when locallyadministered provides localized (regional) full or partial inhibition ofsensory perception and/or motor function. Examples of commonly usedagents suitable for use as anesthetics in the practice of the inventioninclude, but are not limited to ambucaine, amolanone, amylcaine,benoxinate, benzyl alcohol, benzocaine, betoxycaine, biphenamine,bupivacaine, butacaine, butamben, butanilicaine, butethamine,butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine,cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperodon,dyclonine, ecogonidine, ecogonine, etidocaine, euprocin, fenalcomine,formocaine, hexylcaine, hydroxyteteracaine, isobuanine, isobutylp-aminobenzoate, leucinocaine, levobupivacaine, levoxadrol, lidocaine,mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine,naepaine, octacaine, orthocaine, oxethazaine, parenthoxycaine,phenacaine, phenol, piperocaine, piridocaine, polidocanol, pramoxine,prilocaine, procaine, propanocaine, proparacaine, propipocaine,propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol,tetracaine, tolycaine, trimecaine, xylocaine, zolamine, anestheticallyactive derivatives, analogs and any pharmaceutically acceptable saltthereof, and any mixture thereof.

The amide- and ester-type of local anesthetics are preferred for useherein. Amide-type local anesthetics are characterized by having anamide functionality, while ester-type local anesthetics contain an esterfunctionality. Preferred amide-type local anesthetics include lidocaine,bupivacaine, prilocaine, mepivacaine, etidocaine, ropivacaine anddibucaine. Preferred ester-type local anesthetics include tetracaine,procaine, benzocaine and chloroprocaine. The most preferred localanesthetic is bupivacaine.

The anesthetic agent is provided in the composition in a neutral form,as a free base form, or in the form of a pharmaceutically acceptablesalt. The term “pharmaceutically acceptable salt,” as used herein,intends those salts that retain the biological effectiveness andproperties of neutral anesthetics and are not otherwise unacceptable forpharmaceutical use. Pharmaceutically acceptable salts include salts ofacidic or basic groups, which groups may be present in the anestheticagents. Those anesthetic agents that are basic in nature are capable offorming a wide variety of salts with various inorganic and organicacids. Pharmaceutically acceptable acid addition salts of basicanesthetics suitable for use herein are those that form non-toxic acidaddition salts, i.e., salts comprising pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, tartrate, pantothenate, bitartrate,ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Anesthetic agentsthat include an amino moiety may form pharmaceutically acceptable saltswith various amino acids, in addition to the acids mentioned above.Suitable base salts can be formed from bases which form non-toxic salts,for example, aluminium, calcium, lithium, magnesium, potassium, sodium,zinc and diethanolamine salts. See, e.g., Berge et al. (1977) J. Pharm.Sci. 66:1-19.

The ability of an anesthetic agent to provide a condition of sustainedlocal anesthesia refers to the ability of the subject agent to establishan assessable state of localized (regional) full or partial inhibitionof sensory perception and/or motor function. Numerous methods and toolsfor making such an assessment will readily occur to the skilled artisan.With regard to non-human animal subjects, these methods includemeasurement of spontaneous locomotion in test rats (using, for example,commercially available equipment and software from Med Associates Inc.,St. Albans, Vt.), where data can be collected on total distancetraveled, ambulatory counts, stereotypy, rearing, time spent in thevarious motions and time spent at rest for test subjects; visualizationof pin prick reaction in rats; and the rat hotplate foot withdrawalmodel, e.g., according to the procedure described in detail in IACUC No9511-2199.

Sensory testing in human subjects is also a useful way of assessinglocal anesthetic effect. Testing is often focused on three generalareas, mechanical testing (pin prick, von Frey Hairs), thermal (warm,hot, cool) and tactile testing (touch). Such testing techniques aredescribed in the literature. See, for example, Dahl, et al. (1993) Pain53:43-51; Moiniche, et al. (1993) Brit. J. of Anaesthesia 71:201-205;Moiniche, et al. (1993) Regional Anesthesia 18:300-303; Pedersen, et al.(1996) Anesthesiology 84(5):1020-1026; Pedersen, et al. (1996) Brit. J.of Anaesthesia 76(6):806-810; and Pedersen, et al. (1998) Pain74:139-151. For example, the local anesthetic activity of a test agentcan be examined with reference to onset, peak density and duration ofeffect using specific modalities: 1) mechanical sensory testing(mechanical pain detection threshold using von Frey hairs; 2)suprathreshold (mechanical) testing using a single von Frey hair; 3)thermal sensory testing (warm detection threshold); 4) heat paindetection threshold; 5) suprathreshold (heat) testing; 6) cool detectionthreshold; and 7) tactile sensory testing (mechanical touch detectionthreshold). These data are indicative of the subject experiencing localpain relief, local numbness, and or local nerve blockade in response toadministration of a test anesthetic agent. Pain response can becharacterized using a Verbal Rank Scale of 0-10 (e.g., where 0=no pain,and 10=the worst imaginable pain) or a Visual Analog Scale from 0 to 100mm (e.g., where 0=no pain, and 100 mm=worst imaginable pain).

With regard to selection of a particular anesthetic agent, the skilledartisan will also recognize that the pharmacological properties of eachcandidate agent will vary, for example, with respect to onset andintensity of anesthetic effect, duration and the like. Certain agentsmay provide a mild anesthetic effect, having a fairly rapid onset ofactivity, but a short duration. Such agents can be used with thecompositions of the present invention in order to provide an “initialanesthetic effect,” where they are typically paired with a differentanesthetic agent that provides a “sustained local anesthesia,”characterized by a more gradual onset of activity, but a stronger effectand one of longer duration. An example of an anesthetic that can be usedto provide an initial anesthetic effect is benzyl alcohol. An example ofan anesthetic that can be used to provide a sustained local anesthesiais bupivacaine. Still further agents that can be used to provide aninitial anesthetic effect can include organic materials commonly used assolvents and/or penetration agents, such as ethanol, dimethyl sulfoxide,N-methylpyrrolidone, polyethylene glycol and certain fatty acid esters.These and other similar agents can provide a very mild initialanesthetic effect, for example, when applied they can cool or otherwisedesensitize/numb a tissue site, thereby partially inhibiting sensoryperception at that site. Whenever an agent is used in the practice ofthe invention in order to provide an initial anesthetic effect, theagent is provided in a suitable composition in an amount sufficient toprovide the subject effect, and in such as way that the agent is able tobe released from the composition quickly in order to provide theintended effect. Assembly of such suitable compositions (containing anagent for providing an initial anesthetic effect) is within the skill ofthe art when taken in combination with the guidance and teachingprovided by the instant specification.

In certain embodiments of the invention, a composition is provided thatincludes two anesthetic agents, a first anesthetic and a secondanesthetic, wherein the second anesthetic agent is a solvent for thefirst anesthetic agent. In these particular compositions, the secondanesthetic agent is typically used to provide an initial anestheticeffect, and the first anesthetic agent is used to provide a subsequentanesthetic effect characterized by sustained local anesthesia, having anonset within about 2 hours of administration to a subject without aninitial burst, and a duration of at least about 24 hours afteradministration, or even longer. In certain preferred embodiments, thefirst anesthetic agent provides the sustained local anesthesia with anonset within about 1 to 2 hours of administration, and in otherpreferred embodiments, the first anesthetic agent provides the sustainedlocal anesthesia with an onset within about 30 minutes to 1 hour ofadministration. In certain other embodiments, the second anesthetic isalso a solvent for the controlled release carrier system.

An anesthetic agent will serve as a solvent for another anesthetic agentherein when one agent is at least partially dissolved in the othersolvent agent in the manufacture of the composition. In addition, theanesthetic solvent is present in the composition in an amount sufficientto provide both an initial anesthetic effect and at least partiallydissolve the other anesthetic agent. In certain embodiments, the secondanesthetic is thus present in an amount of from about 95 to about 1percent by weight relative to the total weight of the composition (wt%), or in an amount of from about 75 to 10 wt %, or in an amount of fromabout 50 to 15 wt %.

A number of suitable anesthetic agents that also serve as solvents forother anesthetic agents can be used in the practice of the invention.Suitable agents include aromatic alcohols, acids and acid derivatives,and combinations thereof. A particularly preferred anesthetic agent thatcan be used as a solvent for an additional anesthetic is benzyl alcohol.

The controlled release carrier systems employed in the compositions ofthe present invention are classified as non-polymeric carriers. Apharmaceutically acceptable non-polymeric carrier is typicallybiocompatible, and preferably biodegradable, bioerodible, orbioabsorbable. A substance is biocompatible if it and any itsdegradation products present no significant, deleterious or untowardeffects, nor cause substantial tissue irritation or necrosis whenadministered to living tissue. “Biodegradable” or “bioerodible,” usedinterchangeably herein, means the subject non-polymeric material willdegrade or erode in vivo to form smaller chemical species, wherein suchdegradation can result, for example, from enzymatic, chemical, andphysical processes. “Bioabsorbable” means that a given nonpolymericmaterial can be broken down and absorbed within an animal subject'sbody, for example, by a cell, tissue or the like.

The non-polymeric carrier material is used to control release of atleast one anesthetic agent from the compositions of the presentinvention, in such a way as to provide a sustained local anesthesiahaving an onset within about 2 hours of administration and a duration ofat least about 24 hours or longer. In some compositions of the presentinvention, the non-polymeric carrier material is sufficient to provideeither a first order controlled-release profile of the at least oneanesthetic, or a pseudo-zero order release profile. Accordingly, thenon-polymeric carrier will be present in the composition in an amount offrom about 99.5 to about 1 percent by weight relative to the totalweight of the composition (wt %), or in an amount of from about 95 to 10wt %, or in an amount of from about 75 to 25 wt %.

Selection of a suitable non-polymeric carrier is within the generalskill in the art, using the teaching and guidance provided by theinstant disclosure and specification. For example, numerouspharmaceutically acceptable non-polymeric carrier systems are availableto the skilled artisan to produce liquid, spray, cream, lotion,ointment, gel, slurry, oil, emulsion, microemulsion, solid, plaster,film, particle, microparticle, powder or other suitable formpharmaceutical compositions. These and other carrier systems aredescribed, for example, in Remington's Pharmaceutical Sciences, 16^(th)Edition, 1980 and 17th Edition, 1985, both published by Mack PublishingCompany, Easton, Pa.

The compositions of the present invention may further include one ormore additional component, for example pharmaceutically acceptableexcipient materials that can act as dispersing agents, bulking agents,binders, carriers, stabilizers, glidants, antioxidants, pH adjusters,anti-irritants, and the like. The skilled artisan will appreciate thatcertain excipient materials can serve several of the above-referencedfunctions in any particular formulation. Thus, any number of suitableexcipient materials can be mixed with or incorporated into thecompositions of the present invention to provide bulking properties,alter active agent release rates, increase or impede water uptake,control pH, provide structural support, facilitate manufacturingprocesses and other uses known to those skilled in the art. The term“excipient” generally refers to a substantially inert material that isnontoxic and does not interact with other components of the compositionin a deleterious manner. The proportions in which a particular excipientmay be present in the composition depend upon the purpose for which theexcipient is provided and the identity of the excipient.

For example, suitable excipients that can also act as stabilizers foractive agents include pharmaceutical grades of dextrose, sucrose,lactose, trehalose, mannitol, sorbitol, inositol, dextran, and the like.Such stabilizers may thus be a saccharide such as a monosaccharide, adisaccharide, a polysaccharide or a sugar alcohol. Other suitableexcipients include starch, cellulose, sodium or calcium phosphates,calcium sulfate, citric acid, tartaric acid, glycine, and combinationsthereof. Examples of hydrophobic excipients that can be added to slowhydration and dissolution kinetics include fatty acids andpharmaceutically acceptable salts thereof (e.g., magnesium stearate,steric acid, zinc stearate, palimitic acid, and sodium palitate).

It may also be useful to employ a charged lipid and/or detergentexcipient in the compositions of the present invention. Suitable chargedlipids include, without limitation, phosphatidylcholines (lecithin), andthe like. Detergents will typically be a nonionic, anionic, cationic oramphoteric surfactant. Examples of suitable surfactants include, forexample, Tergitol® and Triton® surfactants (Union Carbide Chemicals andPlastics); polyoxyethylenesorbitans, e.g., TWEEN® surfactants (AtlasChemical Industries); polysorbates; polyoxyethylene ethers, e.g. Brij;pharmaceutically acceptable fatty acid esters, e.g., lauryl sulfate andsalts thereof; ampiphilic surfactants (glycerides, etc.); and likematerials.

Other excipient materials can be added to alter porosity, for example,materials like sucrose, dextrose, sodium chloride, sorbitol, lactose,polyethylene glycol, mannitol, fructose, polyvinyl pyrrolidone orappropriate combinations thereof. Additionally, the anesthetic agent oragents may be dispersed with oils (e.g., sesame oil, corn oil,vegetable), or a mixture thereof with a phospholipid (e.g., lecitin), ormedium chain fatty acid triglycerides (e.g., Miglyol 812) to provide anoily suspension.

Still further excipeint materials that can be incorporated into thecompositions of the present invention include diluents of various buffercontent (e.g., Tris-HCl, acetate); pH and ionic strength alteringagents; additives such as antioxidants (e.g., ascorbic acid,glutathione, sodium metabisulfite); preservatives (e.g., Thimersol,benzyl alcohol, methyl paraben, propyl paraben); and dispersing agentssuch as water-soluble polysaccharides (e.g., mannitol, lactose, glucose,starches), hyaluronic acid, glycine, fibrin, collagen and inorganicsalts (e.g., sodium chloride).

In certain embodiments of the invention, the non-polymeric carrier issubstantially insoluble in water or in an aqueous biological system.Exemplary such non-polymeric carrier materials include, but are notlimited to: sterols such as cholesterol, stigmasterol, β-sitosterol, andestradiol; cholestery esters such as cholesteryl stearate; C₁₂-C₂₄ fattyacids such as lauric acid, myristic acid, palmitic acid, stearic acid,arachidic acid, behenic acid, and lignoceric acid; C₁₈-C₃₆ mono-, di-and triacylglycerides such as glyceryl monooleate, glycerylmonolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glycerylmonomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryldidocosanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryltridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glyceroltristearate and mixtures thereof; sucrose fatty acid esters such assucrose distearate and sucrose palmitate; sorbitan fatty acid esterssuch as sorbitan monostearate, sorbitan monopalmitate and sorbitantristearate; C₁₆-C₁₈ fatty alcohols such as cetyl alcohol, myristylalcohol, stearyl alcohol, and cetostearyl alcohol; esters of fattyalcohols and fatty acids such as cetyl palmitate and cetearyl palmitate;anhydrides of fatty acids such as stearic anhydride; phospholipidsincluding phosphatidylcholine (lecithin), phosphatidylserine,phosphatidylethanolamine, phosphatidylinositol, and lysoderivativesthereof; sphingosine and derivatives thereof; spingomyelins such asstearyl, palmitoyl, and tricosanyl spingomyelins; ceramides such asstearyl and palmitoyl ceramides; glycosphingolipids; lanolin and lanolinalcohols; and combinations and mixtures thereof. Certain preferrednon-polymeric carriers include cholesterol, glyceryl monostearate,glycerol tristearate, stearic acid, stearic anhydride, glycerylmonocleate, glyceryl monolinoleate, and acetylated monoglycerides.

If one of the above-noted non-polymeric carrier materials is selectedfor use in a composition of the present invention, it will typically becombined with a compatible and suitable organic solvent for the carriermaterial to form a composition having a consistency ranging from wateryto viscous to a spreadable putty or paste. The consistency of thecomposition will vary according to factors such as the solubility of thenon-polymeric carrier in the solvent, the concentration of thenon-polymeric carrier, the concentration of the anesthetic agent and/orthe presence of additional anesthetic agents, additives and excipients.The solubility of a non-polymeric carrier in a particular solvent willvary according to factors such as its crystallinity, hydrophilicity,ionic character and lipophilicity. Accordingly, the ionic character andthe concentration of the non-polymeric carrier in the solvent can beadjusted to achieve the desired solubility. Preferred non-polymericcarrier materials are those that have low crystallinity, nonpolarcharacteristics, and are more hydrophobic.

Suitable organic solvents for use in the compositions are generallythose that are biocompatible, pharmaceutically acceptable, and will atleast partially dissolve the non-polymeric carrier. The organic solventwill further have a solubility in water ranging from miscible to solubleto dispersible. In certain embodiments, the solvent is selected suchthat it is capable of diffusing, dispersing, or leaching away from thecomposition in situ in an aqueous system and into fluids found at theadministration site, thereby forming a solid implant. Preferably, thesolvent has a Hildebrand (HLB) solubility ratio of from about 9-13(cal/cm³)^(1/2). Preferably, the degree of polarity of the solvent iseffective to provide at least about 5% solubility in water.

Suitable organic solvents thus include, but are not limited to:substituted heterocyclic compounds such as N-methyl-2-pyrrolidone (NMP)and 2-pyrrolidone (2-pyrol); esters of carbonic acid and alkyl alcoholssuch as propylene carbonate, ethylene carbonate and dimethyl carbonate;fatty acids such as acetic acid, lactic acid and heptanoic acid; alkylesters of mono-, di-, and tricarboxylic acids such as 2-ethyoxyethylacetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate,diethyl malonate, diethyl glutonate, tributyl citrate, diethylsuccinate, tributyrin, isopropyl myristate, dimethyl adipate, dimethylsuccinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyltributyl citrate, glyceryl triacetate; alkyl ketones such as acetone andmethyl ethyl ketone; ether alcohols such as 2-ethoxyethanol, ethyleneglycol dimethyl ether, glycofurol and glycerol formal; alcohols such asethanol and propanol; polyhydroxy alcohols such as propylene glycol,polyethylene glycol (PEG), glycerin (glycerol), 1,3-butyleneglycol, andisopropylidene glycol (2,2-dimethyl-1,3-dioxolone-4-methanol); Solketal;dialkylamides such as dimethylformamide, dimethylacetamide;dimethylsulfoxide (DMSO) and dimethylsulfone; tetrahydrofuran; lactonessuch as ε-caprolactone and butyrolactone; cyclic alkyl amides such ascaprolactam; aromatic amides such as N,N-dimethyl-m-toluamide, and1-dodecylazacycloheptan-2-one; and the like; and mixtures andcombinations thereof. Preferred solvents include N-methyl-2-pyrrolidone,2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate,glycofurol, glycerol formal, and isopropylidene glycol.

The organic solvent will be provided in the composition in an amount offrom about 99.5 to about 1 percent by weight relative to the totalweight of the composition (wt %), in an amount of from about 95 to 10 wt%, in an amount of from about 75 to 25 wt %, or in an amount of fromabout 60 to 40 wt %, depending upon the selected non-polymeric carrier,organic solvent, anesthetic agent, additive and/or excipient being usedin the composition. In certain embodiments, the organic solvent diffusesor leaches away from the composition into an aqueous medium uponplacement within a biological system, whereby the non-polymeric carriermaterial coagulates to form a solid matrix. Preferably, thenon-polymeric carrier solidifies in situ to form a solid matrix withinabout 1-5 days after administration (implantation), preferably withinabout 1-3 days, preferably within about 2 hours.

A number of suitable additives may be included with the composition inorder to impart selected characteristics upon the composition. Forexample, the may include a minor amount of a biodegradable thermoplasticpolymer such as a polylactide, polycaprolactone, polyglycolide, orcopolymer thereof, in order to provide a more coherent solid implant ora composition with greater viscosity so as to hold it in place while itsolidifies. Such thermoplastic polymers are disclosed in U.S. Pat. No.4,938,763 to Dunn et al.

Optionally, a pore-forming agent can be included in the composition. Thepore-forming agent can be any organic or inorganic,pharmaceutically-acceptable substance that is substantially soluble inwater or body fluid, and will dissipate from the non-polymeric carriermaterial and/or the solid matrix of an implant into surrounding bodyfluid at the implant site. The pore-forming agent may preferably beinsoluble in the organic solvent to form a uniform mixture with thenon-polymeric carrier material. The pore-forming agent may also be awater-immiscible substance that rapidly degrades to a water-solublesubstance. In certain compositions, the pore-forming agent is combinedwith the non-polymeric carrier and organic solvent in admixture.Suitable pore-forming agents that can be used in the compositioninclude, for example, sugars such as sucrose and dextrose, salts such assodium chloride and sodium carbonate, polymers such ashydroxylpropylcellulose, carboxymethylcellulose, polyethylene glycol andpolyvinylpyrrolidone, and the like. Solid crystals that will provide adefined pore size, such as salt or sugar, are preferred.

In other embodiments of the present invention, compositions are providedwherein the non-polymeric carrier is a liquid. The liquid non-polymericcarrier is preferably a high viscosity liquid carrier material (“HVLCM”)to be non-water soluble, and has a viscosity of at least 5,000 cP, (andoptionally at least 10,000, 15,000; 20,000; 25,000 or even 50,000 cP) at37° C. that does not crystallize neat under ambient or physiologicalconditions. The term “non-water soluble” refers to a material that issoluble in water to a degree of less than one percent by weight underambient conditions. The term “non-polymeric” refers to esters or mixedesters having essentially no repeating units in the acid moiety of theester, as well as esters or mixed esters having acid moieties whereinfunctional units in the acid moiety are repeated a small number of times(i.e., oligomers). Generally, materials having more than five identicaland adjacent repeating units or mers in the acid moiety of the ester areexcluded by the term “nonpolymeric” as used herein, but materialscontaining dimers, trimers, tetramers, or pentamers are included withinthe scope of this term. When the ester is formed from hydroxy-containingcarboxylic acid moieties that can further esterify, such as lactic acidor glycolic acid, the number of repeat units is calculated based uponthe number of lactide or glycolide moieties, rather than upon the numberof lactic acid or glycolic acid moieties, where a lactide repeat unitcontains two lactic acid moieties esterified by their respective hydroxyand carboxy moieties, and where a glycolide repeat unit contains twoglycolic acid moieties esterified by their respective hydroxy andcarboxy moieties. Esters having 1 to about 20 etherified polyols in thealcohol moiety thereof, or 1 to about 10 glycerol moieties in thealcohol moiety thereof, are considered nonpolymeric as that term is usedherein.

In a particular embodiment, the HVLCM decreases in viscosity, in somecases significantly, when mixed with a solvent to form a low viscosityliquid carrier material (“LVLCM”) that can be administered usingstandard medical devices. The LVLCM composition is typically easier toplace in the body than a HVLCM composition, because it flows more easilyinto and out of syringes or other implantation means. It also can easilybe formulated as an emulsion. The LVLCM can have any desired viscosity,but its viscosity is generally lower than the corresponding HVLCM. As anexample, viscosity ranges for the LVLCM of less than approximately 6,000cP, less than approximately 4,000 cP, less than approximately 1,000 cP,or less than 200 cP, are typically useful for in vivo applications.

The particular HVLCM used in the compositions of the invention can beone or more of a variety of materials. Suitable materials includenonpolymeric esters or mixed esters of one or more carboxylic acids. Ina particular embodiment, the ester is formed from carboxylic acids thatare esterified with a polyol having from about 2 to about 20 hydroxymoieties, and which may include 1 to about 20 etherified polyols.Particularly suitable carboxylic acids for forming the acid moiety ofthe ester of the HVLCM include carboxylic acids having one or morehydroxy groups, e.g., those obtained by ring opening alcoholysis oflactones, or cyclic carbonates or by the alcoholysis of carboxylic acidanhydrides. Amino acids are also suitable for forming esters with thepolyol. In a particular embodiment, the ester or mixed ester contains analcohol moiety having one or more terminal hydroxy moieties that havebeen esterified with one or more carboxylic acids obtained byalcoholysis of a carboxylic acid anhydride, such as a cyclic anhydride.

Nonlimiting examples of suitable carboxylic acids that can be esterifiedto form the HVLCM include glycolic acid, lactic acid, ε-hydroxycaproicacid, serine, and any corresponding lactones or lactams, trimethylenecarbonate, and dioxanone. The hydroxy-containing acids may themselves befurther esterified through the reaction of their hydroxy moieties withadditional carboxylic acid, which may be the same as or different fromother carboxylic acid moieties in the material. Suitable lactonesinclude, but are not limited to, glycolide, lactide, ε-caprolactone,butyrolactone, and valerolactone. Suitable carbonates include but arenot limited to trimethylene carbonate and propylene carbonate.

The alcohol moiety of the ester or mixed ester may be derived from apolyhydroxy alcohol having from about 2 to about 20 hydroxy groups, andas indicated above, may be formed by etherifying 1 to 20 polyolmolecules. Suitable alcohol moieties include those derived by removingone or more hydrogen atoms from: monofunctional C₁-C₂₀ alcohols,difunctional C₁-C₂₀ alcohols, trifunctional alcohols, hydroxy-containingcarboxylic acids, hydroxy-containing amino acids, phosphate-containingalcohols, tetrafunctional alcohols, sugar alcohols, monosaccharides, anddisaccharides, sugar acids, and polyether polyols. More specifically,the alcohol moieties may include one or more of: dodecanol, hexanediol,more particularly, 1,6-hexanediol, glycerol, glycolic acid, lactic acid,hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid, serine,ATP, pentaerythritol, mannitol, sorbitol, glucose, fructose, sucrose,glucuronic acid, polyglycerol ethers containing from 1 to about 10glycerol units, polyethylene glycols containing 1 to about 20 ethyleneglycol units.

In particular embodiments of the invention, at least one of thecarboxylic acid moieties of the esters or mixed esters of the HVLCMcomprise at least one oxy moiety In an even more particular embodiment,each of the carboxylic acid moieties comprise at least one oxy moiety.

In another particular embodiment, at least one of the carboxylic acidmoieties of the esters or mixed esters of the invention contains 2 to 4carbon atoms. In an even more particular embodiment, each of thecarboxylic acid moieties of the esters or mixed esters of the inventioncontains 2 to 4 carbon atoms.

In another more particular embodiment of the invention, at least one ofthe carboxylic acid moieties of the ester or mixed ester of theinvention has 2 to 4 carbon atoms and contains at least one oxy moiety.In another more particular embodiment of the invention, each of thecarboxylic acid moieties of the ester or mixed ester of the inventionhas 2 to 4 carbon atoms and contains at least one oxy moiety.

In a particular embodiment, the HVLCM may be sucrose acetate isobutyrate(SAIB) or some other ester of a sugar alcohol moiety with one or morealkanoic acid moieties.

In a particular embodiment, the invention includes compositions whereinthe HVLCM has a structure selected from the group consisting of:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently selectedfrom the group consisting of hydrogen, alkanoyl, hydroxy-substitutedalkanoyl, and acyloxy-substituted alkanoyl;

wherein at least three of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are otherthan hydrogen; and

wherein when R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are selected from thegroup consisting of acetyl and isobutyryl, at least three of R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are acetyl;

wherein R¹, R², and R³ are independently selected from the groupconsisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, andacyloxy-substituted alkanoyl and wherein n is between 1 and 20; III:

R¹—O—(CH₂)_(n)—O—R²

wherein n is an integer between 4 and 8, and R¹ and R² are independentlyselected from the group consisting of hydrogen, alkanoyl,hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl;

wherein in formulae IV and V, R¹, R², R³, R⁴, and R⁵ are independentlyselected from the group consisting of hydrogen, alkanoyl,hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl;

wherein in formulae VI and VII, R¹, R², R³, R⁴, R⁵, and R⁶ areindependently selected from the group consisting of hydrogen, alkanoyl,hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl;

wherein R¹, R², R³, and R⁴ are independently selected from the groupconsisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, andacyloxy-substituted alkanoyl.

In each of formulae I through VIII, one or more of the alkanoyl,hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl groupsmay comprise alkanoyl moieties having 2 to 6 carbon atoms, including thecarbonyl carbon. Moreover, in another more particular embodiment of theinvention, each of formulae I through VIII comprise at least onehydroxy-substituted or acyloxy-substituted alkanoyl moiety. In an evenmore particular embodiment, at least one of these hydroxy-substituted oracyloxy-substituted alkanoyl moieties comprise alkanoyl moieties having2 to 6 carbon atoms, including the carbonyl carbon.

The acyl groups forming the acyloxy substituents of the HVLCM may be anymoiety derived from a carboxylic acid in accordance with the commonlyaccepted definition of the term “acyl.” More particularly, the acylgroups of the compositions of the invention may be of the form R⁹CO—,where R⁹ is optionally oxy-substituted alkyl of 2-6 carbon atoms. Thisoxy-substitution may take the form of hydroxy substitution, orsubstitution with additional acyl moieties. For example R⁹ may be anoligomer of oxy-substituted carboxylic acids, linked by ester bondingbetween the hydroxy of one acid and the carboxy of another acid. In amore particular example, R⁹ may comprise 1 to 5 lactide or glycolideunits, where a lactide unit contains two lactic acid moieties esterifiedtogether and a glycolide unit contains two glycolic acid moietiesesterified together. Alternatively, R⁹ may contain mixed lactide andglycolide units, or may contain mixed lactic acid and glycolic acid,without the presence of lactide or glycolide units.

Particular HVLCM materials include components according to formulae IIor III, wherein R¹, R², and R³ are independently lactoyl, polylactoyl,ε-caproyl, hydroxyacetyl, or polyhydroxyacetyl, in particular,polylactoyl and ε-caproyl, or polylactoyl and polyhydroxyacetyl.

The use of relatively small chain (2 to 6 carbon atoms), oxy-substitutedcarboxylic acid moieties in the ester or mixed ester of the invention isadvantageous. When these acid moieties are present in the form ofoligomeric esters (i.e., a subsequent acid moiety joined to the previousacid moiety through esterification of the subsequent carboxy with theprevious oxy), hydrolysis of the material is considerably easier thanfor oligomers made with more than 6 carbon atoms because the material ismore hydrophilic. In general, for drug delivery it is desired that theHVLCM be water insoluble, but it may be somewhat hydrophilic. Ingeneral, HVLCMs synthesized with more hydrophilic units (as determinedby a higher O:C ratio) will be expected to absorb water more rapidly anddegrade more quickly. For example, a HVLCM made by covalently linking 4moles of glycolide to one mole of glycerol will be expected to absorbwater more rapidly and degrade more quickly than a HVLCM made bycovalently linking 2 moles of glycolide and 2 moles of lactide to onemole of glycerol. Similar increases can be expected for more flexiblemolecules and for more branched, spherical molecules based on freevolume arguments. Use of flexible and branched molecules may also havethe benefit of lowering the viscosity of the LVLCM. Using carboxylicacids and/or polyols of different chain length and using carboxylicacids having oxy-substitution allows a precise control of the degree ofhydrophilicity and of the solubility of the resulting ester. Thesematerials are sufficiently resistant to dissolution in vivo that theyare able to provide a controlled release of a carried anesthetic agentinto the body accompanied or followed by oxy bonds hydrolyzing in vivo.

In an even more particular embodiment, the HVLCM excludes the acetateand isobutyrate ester of sucrose having a ratio of acetate toisobutyrate acid moieties of 2:6. However, sucrose acetate isobutyrateester having a ratio of acetate to isobutyrate moieties of 2:6 isincluded within the scope of the invention for use in aerosolformulations. This material can be made according to the proceduresdescribed in U.S. Pat. No. 2,931,802.

In general, suitable HVLCM esters can be made by reacting one or morealcohols, in particular one or more polyols, which will form the alcoholmoiety of the resulting esters with one or more carboxylic acids,lactones, lactams, carbonates, or anhydrides of the carboxylic acidswhich will form the acid moieties of the resulting esters. Theesterification reaction can be conducted simply by heating, although insome instances addition of a strong acid or strong base esterificationcatalyst may be used. Alternatively, an esterification catalyst such asstannous 2-ethylhexanoate can be used. The heated reaction mixture, withor without catalyst, is heated with stirring then dried, e.g., undervacuum, to remove any un-reacted starting materials and produce a liquidproduct. Sucrose acetate isobutyrates can be made by following theprocedures described in U.S. Pat. No. 2,931,802.

In this regard, the polyol can be viewed as an oligomerizationinitiator, in the sense that it provides a substrate for esterificationof carboxylic acids, in particular, of oligomers of lactide, glycolide,or other esterified hydroxy-substituted carboxylic acids.

In certain embodiments, the HVLCM can be mixed with a viscosity-loweringsolvent to form a lower viscosity liquid carrier material (LVLCM), whichcan then be mixed with the one or more anesthetic agent to be delivered,prior to administration. These solvents can be water soluble, non-watersoluble, or water miscible, and can include, acetone, benzyl alcohol,benzyl benzoate, N-(betahydroxyethyl) lactamidebutylene glycol,caprolactam, caprolactone, corn oil, decylmethylsulfoxide, dimethylether, dimethyl sulfoxide, 1-dodecylazacycloheptan-2-one, ethanol, ethylacetate, ethyl lactate, ethyl oleate, glycerol, glycofurol(tetraglycol), isopropyl myristate, methyl acetate, methyl ethyl ketone,N-methyl-2-pyrrolidone, MIGLYOLs® (esters of caprylic and/or capricacids with glycerol or alkylene glycols, e.g., MIGLYOL® 810 or 812(caprylic/capric triglycerides), MIGLYOL® 818 (caprylic/capric/linoleictriglyceride), MIGLYOL® 829 (caprylic/capric/succinic triglyceride),MIGLYOL® 840 (propylene glycol dicaprylate/caprate)), oleic acid, peanutoil, polyethylene glycol, propylene carbonate, 2-pyrrolidone, sesameoil, SOLKETAL ([±]-2,2-dimethyl-1,3-dioxolane-4-methanol),tetrahydrofuran, TRANSCUTOL® (diethylene glycol monoethyl ether,carbitol), triacetin, triethyl citrate, diphenyl phthalate, andcombinations thereof. Additionally, if the composition is to be appliedas an aerosol, e.g. for topical application, the solvent may be or mayinclude one or more propellants, such as CFC propellants liketrichlorofluoromethane and dichlorofluoromethane, non-CFC propellantslike tetrafluoroethane (R-134a), 1,1,1,2,3,3,3-heptafluoropropane(R-227), dimethyl ether, propane, and butane.

Particularly suitable solvents and/or propellants include benzylbenzoate, benzyl alcohol, triacetin, triethyl citrate, dimethylsulfoxide, ethanol, ethyl lactate, glycerol, glycofurol (tetraglycol),N-methyl-2-pyrrolidone, MIGLYOL® 810, polyethylene glycol, propylenecarbonate, 2-pyrrolidone, and tetrafluoroethane.

Other possible solvents include perfluorodecalin,perfluorotributylamine, methoxyflurane, glycerolformal,tetrahydrofurfuryl alcohol, diglyme, and dimethyl isosorbide.

When the composition is used as a LVLCM to administer the anestheticagent, it should contain a solvent that the HVLCM is soluble in. Incertain instances, the anesthetic agent is also soluble in the solvent.In still further instances, the solvent is a second anesthetic agent inwhich the first anesthetic agent is soluble. The solvent is preferablynon-toxic and otherwise biocompatible.

In certain embodiments, the solvent is at least water soluble, so thatit will diffuse quickly into bodily fluids or other aqueous environmentupon administration, causing the composition to coagulate and/or becomemore viscous. In another embodiments, the solvent is not completelymiscible with water or bodily fluids so that diffusion of the solventfrom the composition, and the corresponding increase in viscosity of thecomposition, are slowed. Suitable solvents that have this property, atleast to some extent, include benzyl benzoate, MIGLYOL® 810, benzylalcohol, and triethylcitrate. Benzyl alcohol can be particularlysuitable, as it also an anesthetic agent.

When esters of 1,6-hexanediol or glycerol are used as the HVLCM, somepossible solvents are ethanol, N-methylpyrrolidone, propylene carbonate,and PEG 400.

The solvent is typically added to the compositions in an amount in therange from about 99.7 percent to about 0.5 percent by weight relative tothe total weight of the composition (wt %), from about 95 percent toabout 1 wt %, from about 75 to about 10 wt %, or from about 50 to 15 wt%. The solvent is typically present in the composition in an amount inthe range from about 55 percent to 10 wt %.

In still further embodiments of the invention, the composition includesa material that is not miscible with the HVLCM, such that when combinedwith the HVLCM singularly or in combination with a solvent for theHVLCM, the resulting composition forms an emulsion. Such emulsions maycontain the HVLCM in the dispersed phase, such as in the case ofSAIB/MIGLYOL® mixtures that are emulsified in water or glycerol, or theymay contain the HVLCM as a component of the continuous phase, such as inthe case of an aqueous solution that is emulsified in the HVLCM or asolution of the HVLCM in a water immiscible solvent.

Any of the above-described non-polymeric controlled delivery systems canbe formulated as liquid, spray, cream, lotion, ointment, gel, slurry,oil, emulsion, microemulsion, solid, plaster, film, particle,microparticle, powder or other suitable form pharmaceuticalcompositions, suitable for use in the methods of the present invention.In such compositions, the anesthetic agent (e.g., the first anestheticagent) is included in an amount sufficient to deliver to the subject tobe treated an effective amount to achieve a desired effect. The amountof anesthetic agent incorporated into the composition depends upon thefinal desired release duration and profile, and the concentration ofanesthetic required for the intended effect.

The concentration of the anesthetic in the composition will also dependon absorption, inactivation, and excretion rates of that particularagent, as well as other factors known to those of skill in the art. Itis to be noted that dosage values will also vary with the severity ofthe condition to be alleviated. It is to be further understood that forany particular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The composition may be administered in onedosage, or may be divided into a number of smaller doses to beadministered at varying intervals of time, either sequentially orconcurrently.

The anesthetic agent or agents will typically be present in thecomposition in the range from about 0.1 to about 99.5 percent by weightrelative to the total weight of the composition (wt %), from about 0.5to about 70 wt %, or from about 1 percent to about 50 wt %. However,ranges having upper endpoints as low as about 40%, 30%, 20%, or 10% canbe used, as can ranges having lower limits as high as about 5%, 3%, or2%. For very active anesthetic agents, the ranges may be less than 1% byweight, and possibly less than 0.0001%.

Both soluble and insoluble anesthetic agents can be distributed usingthe non-polymeric carrier materials for controlled delivery. Moreover,the compositions may be further formulated with polymeric excipients toprovide a delivery matrix with modified properties, for example a fasteror slower degradation rate. The resulting composition may be formed intomicrospheres, or into a macroscopic implant, or other geometries andsizes according to techniques known in the art. Alternatively, apre-formed microsphere, implant, or polymer particle with the anestheticagent or agents incorporated therein can be combined with thenon-polymeric carrier.

Microspheres may be prepared by a number of methods known in the art, aswell as methods described in U.S. Pat. Nos. 6,291,013 and 6,440,493. Thepolymer particle may be formed using melt extrusion, granulation,solvent mixing, absorption, or like techniques, or the anesthetic agentmay be adsorbed onto a polymer matrix, such as an ion exchange resin.The resulting material, when combined suitable non-polymeric carriermaterial may be administered parenterally. In other embodiments, theanesthetic agent may be combined with a non-polymeric material, such ascalcium phosphate or sucrose, to provide layering/barrier propertiesthat lengthen degradation. The non-polymeric carrier will then form asecondary barrier to provide enhanced delivery characteristics. Thenon-polymeric carrier phase may or may not contain other biologicallyactive substances, according to the specific requirement of the selectedapplication. These other biologically active agents may be any suitabletherapeutic and/or prophylactic pharmaceutical, provided that the addedsubstance is suitable for incorporation into microspheres or implantsaccording to techniques known in the art.

As discussed above, a variety of additives can optionally be added tothe compositions of the present invention to modify the propertiesthereof, and in particular to modify the release properties of thecomposition with respect to the anesthetic agents contained therein. Theadditives can be present in any amount sufficient to impart the desiredproperties to the composition. The amount of additive used will ingeneral be a function of the nature of the additive and the effect to beachieved, and can be easily determined by the routineer. Suitableadditives are described in U.S. Pat. No. 5,747,058, the entire contentsof which are hereby incorporated by reference. More particularly,suitable additives include water, biodegradable polymers,non-biodegradable polymers, natural oils, synthetic oils, carbohydratesor carbohydrate derivatives, inorganic salts, BSA (bovine serumalbumin), surfactants, organic compounds, such as sugars, and organicsalts, such as sodium citrate. In general, the less water soluble, i.e.,the more lipophilic, the additive, the more it will decrease the rate ofrelease of the anesthetic agent, compared to the same compositionwithout the additive. In addition, it may be desirable to includeadditives that increase properties such as the strength or the porosityof the composition.

The addition of additives can also be used to lengthen the delivery timefor the anesthetic agent, making the composition suitable for medicalapplications requiring or responsive to longer-term administration.Suitable additives in this regard include those disclosed in U.S. Pat.Nos. 5,747,058 and 5,736,152. In particular, suitable additives for thispurpose include polymeric additives, such as cellulosic polymers andbiodegradable polymers. Suitable cellulosic polymers include celluloseacetates, cellulose ethers, and cellulose acetate butyrates. Suitablebiodegradable polymers include polylactones, polyanhydrides, andpolyorthoesters, in particular, polylactic acid, polyglycolic acid,polycaprolactone, and copolymers thereof.

When present, the additive is typically present in the compositions inan amount in the range from about 0.01 percent to about 20 percent byweight, more particularly from about 0.1 percent to about 20 percent byweight, relative to the total weight of the composition, and moretypically, is present in the composition in an amount in the range fromabout 1, 2, or 5 percent to about 10 percent by weight. Certainadditives, such as buffers, are only present in small amounts in thecomposition.

The following categories are nonlimiting examples of classes ofadditives that can be employed in the compositions of the presentinvention.

One category of additives are biodegradable polymers and oligomers. Thepolymers can be used to alter the release profile of the anestheticagent to be delivered, to add integrity to the composition, or tootherwise modify the properties of the composition. Non-limitingexamples of suitable biodegradable polymers and oligomers include:poly(lactide), poly(lactide-co-glycolide), poly(glycolide),poly(caprolactone), polyamides, polyanhydrides, polyamino acids,polyorthoesters, polycyanoacrylates, poly(phosphazines),poly(phosphoesters), polyesteramides, polydioxanones, polyacetals,polyketals, polycarbonates, polyorthocarbonates, degradablepolyurethanes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkyleneoxalates, polyalkylene succinates, poly(malic acid), chitin, chitosan,and copolymers, terpolymers, oxidized cellulose, or combinations ormixtures of the above materials.

Examples of poly(α-hydroxy acid)s include poly(glycolic acid),poly(DL-lactic acid) and poly(L-lactic acid), and their copolymers.Examples of polylactones include poly(ε-caprolactone),poly(δ-valerolactone) and poly(γ-butyrolactone).

While not wishing to be bound by any theory, it is believed that whenthe composition contains a biodegradeable polymer, a portion of thepolymer may precipitate or coagulate at the surface of the compositionas any included solvent diffuses away from the material afteradministration to the subject. The polymer may thus be added as arelease modifying agent to affect the release of the anesthetic agent oragents, or may be added as part of a composition containing pre-formedmicrospheres, implants, or ground polymer particles. The precipitationor coagulation of the polymer forms a skin at least partiallysurrounding the liquid core of such composition. This skin is porous,and allows the solvent to continue to diffuse through it intosurrounding tissue. The rate of solvent release and the extent offormation of the skin, as well as its porosity, can be controlled by theamount and type of solvent and polymer used in the composition.

Other additives for use with the present compositions arenon-biodegradable polymers. Non-limiting examples of nonerodiblepolymers which can be used as additives include: polyacrylates,ethylene-vinyl acetate polymers, cellulose and cellulose derivatives,acyl substituted cellulose acetates and derivatives thereof,non-erodible polyurethanes, polystyrenes, polyvinyl chloride, polyvinylfluoride, polyvinyl (imidazole), chlorosulphonated polyolefins,polyethylene oxide, and polyethylene.

Preferred non-biodegradable polymers include polyvinyl pyrrolidone,ethylene vinylacetate, polyethylene glycol, cellulose acetate butyrate(“CAB”) and cellulose acetate propionate (“CAP”).

A further class of additives which can be used in the presentcompositions are natural and synthetic oils and fats. Oils derived fromanimals or from plant seeds of nuts typically include glycerides of thefatty acids, chiefly oleic, palmitic, stearic, and linoleic. As a rulethe more hydrogen the molecule contains the thicker the oil becomes.

Non-limiting examples of suitable natural and synthetic oils includevegetable oil, peanut oil, medium chain triglycerides, soybean oil,almond oil, olive oil, sesame oil, fennel oil, camellia oil, corn oil,castor oil, cotton seed oil, and soybean oil, either crude or refined,and medium chain fatty acid triglycerides.

Fats are typically glyceryl esters of higher fatty acids such as stearicand palmitic. Such esters and their mixtures are solids at roomtemperatures and exhibit crystalline structure. Lard and tallow areexamples. In general oils and fats increase the hydrophobicity of anon-polymeric carrier system, slowing degradation and water uptake.

All of the above-described compositions may be used in the methods ofthe present invention in order to provide sustained local anesthesia ata target site. In particular, the compositions may be formulated asliquid, spray, cream, lotion, ointment, gel, slurry, oil, emulsion,microemulsion, solid, plaster, film, particle, microparticle, powder orany other suitable pharmaceutical composition form and then administeredto a subject via topical, transdermal, parenteral (e.g, injection,implant, etc.) or like delivery techniques. The compositions, containingan anesthetic and a pharmaceutically acceptable non-polymeric carrier,are used to provide an anesthetic effect characterized by sustainedlocal anesthesia after administration to the subject without an initialburst and a duration of at least about 24 hours after administration,preferably at least about 36 to 48 hours after administration, and morepreferably at least about 48 to 72 hours after administration. Incertain embodiments, the onset of the local anesthesia occurs withinabout 2 hours of administration to the subject, preferably within about1 hour of administration, and in some cases within about 30 minutes ofadministration to the subject.

The term “subject,” as used herein, refers to any vertebrate in which itis desired to provide a state of local anesthesia. The term thus broadlyrefers to any animal that is to be treated with the compositions of thepresent invention, such as birds, fish and mammals including humans. Incertain embodiments, the methods of the present invention are suitableto provide sustained anesthesia in veterinary practice and animalhusbandry, e.g., birds and mammals, whenever a long-term state of localanesthesia is convenient or desirable. In certain cases, thecompositions are particularly suited for used with companion animalssuch as dogs or cats, and additionally may be used with horses. Inpreferred embodiments, the term “subject” intends a human subject.Furthermore, the term “subject” does not denote a particular age, andthe compositions are thus suited for use with subjects of any age, suchas infant, adolescent, adult and senior aged subjects.

In preferred embodiments, the compositions of the present invention areparticularly suited for use in the treatment of wounds. Thenon-polymeric carrier systems allow the anesthetic agent or agents to beeasily applied to the wound, either directly within the wound and/oradjacent to the wound, using very simple application techniques suchdropping on, spraying, painting, spreading, molding or otherwisemanually manipulating a liquid, spray, cream, lotion, ointment, gel,slurry, oil, emulsion, microemulsion, pliable solid or plaster, film,particle, microparticle, or powder composition into the wound. Thecompositions can thus be used with any sized or shaped wound, and willprovide an even distribution of the anesthetic agent or agents over theentire area of the wound for better retention and efficacy. Wounds thatcan be treated using such methods my range for the most superficial todeep, from surface to incisional and from surgical (or otherwisedeliberate) to accidental. If the composition is to be injected, it maybe applied to the subcutaneous space using a trailing injectionalongside the wound on all sides or outside boundaries. Combinationapproaches may also be employed, such as where the composition is bothlaid directly into the wound, e.g., prior to surgical closure of thesound, and additionally along the wound. In a particularly preferredembodiment, the methods of the invention involve the use of the instantcompositions as a local anesthetic for treatment of post-operativeincisional pain. Use of the present compositions in this manner mayobviate or at least mitigate the necessity to provide adjunct therapies,such as the administration of systemic narcotic analgesics in order totreat such post-operative pain. Accordingly, the compositions may beused to treat post-operative pain that accompanies all types of medicalprocedures, such as major surgeries (e.g. thoracotomy, aortic repair,bowel resection), intermediate surgeries (e.g., cesarean section,hyseterectomy and appendectomy), and minor surgeries (laparoscopy,arthroscopy, and biopsy procedures), that can otherwise be debilitatingand may require pain treatment for 3 to 5 days after surgery.

The compositions described herein can thus be administered in thepractice of the instant methods using a wide variety of methods. Forexample, the compositions may be administered topically, systematically(for example, mucosally (orally, rectally, vaginally, or nasally),parenterally (intravenously, subcutaneously, intramuscularly, orintraperitoneally), or the like. The compositions may be applied viainjection, pouring, spray dip, aerosol, or coating applicator. Aerosolsor mists of the composition can be administered using an aerosolpropellant, e.g., for topical administration, or using a suitablenebulizer, e.g., for nasal, or oral mucosal administration.

Preferably, the compositions are administered as liquids via injection,or in an aerosol, paste or emulsion. When used in an aerosol, anysolvent present in the aerosol solution will typically evaporate uponapplication, allowing the composition to set-up as a film.Alternatively, the aerosol or emulsion may be prepared without asolvent. In this situation, the aerosol propellant can also function asa solvent. Formation of aerosols and emulsions can be accomplished usingtechniques known to those skilled in the art. See, for example, Ansel,H. C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems,Sixth Edition (1995).

In addition to the uses described above, the present compositions can beadministered through osmotic pumps. In one embodiment, a device isdesigned to be implanted in the tissue of the subject, and designed toeffect sustained release over time.

It is also possible to administer the compositions of the inventionusing a porous or nonporous tube, desirably made of extrudedbiodegradeable polymer. The tube may be prepared with varying degrees ofporosity depending on the characteristics of the composition and therelease characteristics desired. The composition of the invention isinserted into the tube, and the ends of the tube may be left open,allowing biologically active compound to diffuse out of the ends of thetube, or may be closed off with additional porous or nonporous polymer.Porous endcaps and porous tubes allow active compound to diffuse throughthe pores over time. Nonporous endcaps, as well as nonporous tubes,allow anesthetic agents that are soluble in the polymer to diffusethrough it and into surrounding tissues. Nonporous materials that arenot solvents for the anesthetic, but that are biodegradable, willrelease the anesthetic when they degrade sufficiently. The compositionsof the invention may be prepared and stored as multi-component systemsuntil ready for administration. The number of different components willdepend, in part, on the characteristics of the composition. Prior toadministration, the components are combined and mixed, e.g., to achievea homogeneous composition, which can then be administered to thesubject. Solvents or additives may be added to one or all of thecomponents, or may form a separate component, which is also mixed withthe others prior to administration. Separation of the composition into amulticomponent mixture allows the storage conditions for each componentto be optimized, and minimizes any detrimental interactions betweencomponents over time. The result is increased storage stability.

EXAMPLES

Below are examples of specific embodiments for carrying out the presentinvention. The examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.

General Methods

The in-vivo efficacy of the compositions and methods of the inventionmay be assessed in the rat using a hotplate model, e.g., according tothe procedure described in detail in IACUC No 9511-2199. The efficacycriteria established for compositions of the invention are mean latencygreater than about 2 seconds, with a 12 second cut-off (this cutoff isimposed to prevent any possible damage to the animal). Latencies at 2seconds are demonstrative of a statistically significant effect of thelocal anesthetic. Preferably, the mean latency under the rat hotplatemodel is greater than 7 seconds. Preferably, the percent responders is50% or greater. Preferably, the compositions of the invention provide amean latency under the rat hotplate model greater than about 7 secondsto about 12 seconds, with the percent of rats exhibiting the effectbeing at least about 50% of those tested.

The rat hotplate methodology is summarized as follows. Male SpragueDawley rats (Harlan Laboratories, Indianapolis, Ind.) with an averageweight of 275 gm are used. The hotplate study consists of gently holdingthe body of the animal while the plantar surface of the hind paw isplaced on a hotplate heated to 56° C. Baseline latency is determinedprior to unilateral injection of anesthetic composition around thesciatic nerve of the rat.

Sensory testing in human models is also useful in the testing of thecompositions of the present invention. The local anesthetic activity canbe examined with reference to onset, peak density and duration of effectusing seven specific modalities: (a) mechanical sensory testing(mechanical pain detection threshold using von Frey hairs; (b)suprathreshold (mechanical) testing using a single von Frey hair; (c)thermal sensory testing (warm detection threshold); (d) heat paindetection threshold; (e) suprathreshold (heat) testing; (f) cooldetection threshold; and (g) tactile sensory testing (mechanical touchdetection threshold). The varying degrees or levels of the results willbe indicative of the subject experiencing local pain relief, localnumbness, and or local nerve blockade. The anesthetic activity of thecompositions and methods of the invention can be further characterizedwith respect to safety, by various measures of activity such as systemicblood plasma levels attained after administration at the localized site.

Mechanical pain detection threshold is defined as the lowest force ornumber of a von Frey Hair which produces a definite sensation of pain ordiscomfort, and Mechanical touch detection threshold is defined as thelowest force or number of a von Frey Hair which produces a sensation oftouch or pressure. Mechanical Touch Detection Threshold and MechanicalPain Detection Thresholds can be determined simultaneously usingprogressively rigid von Frey Hairs (VFH) (available from Somedic A/B,Stockholm, Sweden). It ha previously been determined that each VFHpressed against a balance until it slightly flexed represents a forcewhich logarithmically increases with each hair, covering a total rangeof 3 to 402 milliNewtons (mN) (VFH No. 7=3 mN; VFH No. 8=13 mN; VFH No.9=20 mN; VFH No. 10=39 mN; VFH No. 11=59 mN; VFH No. 12=98 mN; VFH No.13=128 mN; VFH No. 14=133 mN; VFH No. 15=314 mN; VFH No. 16=350 mN; VFHNo. 17=402 mN).

Accordingly, in a human subject, an area injected with a compositionproduced according to the present invention can be stimulated 8 timeswith each VFH at a rate of about 2 stimuli per second, starting with VFHNo. 7 and moving to VFH No. 17. The lowest VFH number that is sensed astouch or pressure (Mechanical Touch Detection Threshold) and the lowestnumber of the hair in which half of the eight stimulations are painfulor unpleasant (Mechanical Pain Detection Threshold) are recorded. Theprocedure is repeated two more times and the median of the threemeasurements is reported. If VFH No. 17 does not produce the sensationof touch or pressure a Mechanical Touch Detection Threshold value of 18will be assigned. If VFH No. 17 does not produce any pain or discomforta Mechanical Pain Detection Threshold value of 18 will be assigned.Suprathreshold Pain Response-Mechanical to a single von Frey Hair isdetermined by stimulating the injected areas five times with VFH No. 17(402 mN). The subject assesses the pain using a VRS scale of 0-10, wherezero (0)=no pain, and ten=(10) pain as intense as imaginable.

As discussed above, this test is conducted with a single rigid von FreyHair that is determined to produce a painful response in subjects. Painresponse is determined by stimulating an injected or otherwise treatedarea 5 times with VFH No. 17. Subjects rate pain on the Verbal RankScale (VRS) of 0 to 10, as above.

Thermal testing (Suprathreshold Pain Response-Heat) in a treated area isdetermined by a stimulus of 45° C., lasting 5 seconds using acomputerized thermode (available from Thermostest, Somedic A/B,Stockholm, Sweden) on treated areas. The subject assesses pain on aVerbal Rank Scale (VRS) of 0-10.

Warm Detection Threshold is defined as the lowest increase intemperature from 32° C. perceived, Heat pain Detection Threshold isdefined as the lowest temperature perceived as painful, and CoolDetection Threshold is defined as the lowest decrease in temperaturefrom 32° C. perceived. Warm Detection Threshold, Heat Pain DetectionThreshold and Cool Detection Threshold are determined with acomputerized Thermostest (available from Somedic A/B, Stockholm, Sweden)in treated areas. Subjects are instructed to press a button as soon asthe specified sensation is reached. Thermal thresholds are determinedfrom a baseline of 32° C. and increased (Warm Detection Threshold andHeat Pain Detection Threshold) or decreased (Cool Detection Threshold)at a rate of change of 1° C. per second. The upper cut off limit is 52°C. for Warm Detection Threshold and Heat Pain Detection Threshold. Thelower cut off limit is 25° C. for Cool Detection Threshold.

Warm Detection Threshold, Heat Pain Detection Threshold and CoolDetection Threshold are calculated as the median of three measurements,with intervals of 10 seconds between each stimulus. If the subject hasnot perceived warmth or pain at 52° C., the value 53° C. is recorded forWarm Detection Threshold; if the subject has not perceived pain by 52°C., the value of 53° C. is recorded for Heat Pain Detection Threshold;and if the subject has not perceived coolness or pain at 25° C., thevalue 24° C. is recorded for Cool Detection Threshold.

Example 1

A non-polymeric liquid carrier system containing an anesthetic agent wasproduced as follows. Sucrose acetate isobutyrate (SAIB) was combinedwith a N-methylpyrrolidone (NMP) solvent for the SAIB carrier to providea 70:30 mixture. To this mixture either 2.5% (w/v) or 5% bupivacaine(free base) was added to provide two test compositions.

Male Sprague Dawley Rats, (275 to 300 g) were split into two test groupsof 8 animals each. The test formulations were administered into thequadrupeds using needle and syringe to deliver either 25 or 50 mg dosesof the bupivacaine. The skin flinch response test was then used todetermine the presence of a local anesthetic effect, wherein involuntaryflinch upon cutaneous stimulation using a pin applied to 10 random areaswithin 1 cm of the base of the injection site. Percent inhibition ofpin-perception was then calculated by taking the baseline response minusthe test response, divided by the baseline response and multiplied by100.

The results obtained indicated that both test compositions providedlocal anesthetic effect for up to about 60-72 hours duration, with anonset of activity within 1 hour of administration.

Example 2

Subjects. Male, Fisher 344 rats (Charles River Laboratories) (N=96) wereused for the study. Animals were kept on a reversed light:dark cycle(dark 5:00 to 17:00) in a temperature and humidity controlled vivarium.Rats were given ad lib access to food and water except duringexperimental sessions. All experiments were conducted during the darkphase of the light:dark cycle. All procedures were approved by theInstitutional Animal Care and Use Committee of Wake Forest UniversityHealth Sciences Center.

Surgical procedure. Following induction of anesthesia with 5% isofluranevapor in oxygen, animals were shaved on the left lower quadrant of theabdomen. Anesthesia was maintained throughout the surgical procedureusing 2.0 to 2.5% isoflurane vapor in oxygen. A 3 cm incision was placed0.5 cm below and parallel to the lowest rib on the left side,penetrating into the peritoneal cavity. The viscera and musculature werevigorously manipulated by inserting 5 to 7 cm of the index finger intothe peritoneal cavity and stretching the musculature. Approximately 10cm of the small intestine was exteriorized and gently manipulated. Theintestine was placed inside the peritoneal cavity and the wound wassutured in 3 layers consisting of the peritoneal lining, abdominalmuscles and skin using 4.0 chromic gut. Exterior wounds were dressedwith antibiotic powder (Polysporin®, Glaxo-Wellcome, Research TrianglePark, N.C.) and animals were given 75,000 U of penicillin G procainei.m. Sham-treated animals were anesthetized, shaved, maintained underisoflurane anesthesia for 20 min and given penicillin G procaine i.m.

Administration of the controlled release bupivacaine composition. Testanimals were administered either vehicle (70:30, SAIB:NMP), 1.25% (w/v),2.5% or 5% bupivicaine according to table 1. The composition wasadministered following suturing of the skin using a trailing injectiontechnique with a 1.0 ml syringe and a 1.5 in 22 ga needle such that 0.25ml of the composition was evenly distributed over the incision area atapproximately 0.5 cm above the wound site. A second administration wasgiven in a similar manner 0.5 cm below the wound site. For groups K andL, an additional administration of 0.1 ml of either 1.25% (w/v) or 5%bupivicaine was given on top of the peritoneal lining using the trailinginjection technique prior to suturing the outer muscle layer. Thebupivicaine composition was allowed to remain on the peritoneal liningfor 1 to 2 min prior to suturing the outer muscle to achieve sufficientviscosity and thereby prevent the composition from leaching through theouter muscle during the suturing process.

TABLE 1 Groups were treated as described below. All groups, with theexception of group B, received surgical laparotomy as described above.Group Treatment AA No treatment BB Sham surgery CC 0.5 ml Vehicle DD 0.5ml 1.25% bupivicaine EE 0.5 ml 2.5% bupivicaine FF 0.5 ml 5% bupivicaineGG 0.1 ml inner, 0.5 ml outer 1.25% bupivicaine HH 0.1 ml inner, 0.5 mlouter 5% bupivicaine

Measurement of Spontaneous Locomotion. Exploratory behavior was assessedbeginning 24 hr after laparotomy using commercially available equipmentand software (Med Associates Inc., St. Albans, Vt.). Activity chambersconsisted of acrylic enclosures measuring 17″×17″ that were 15″ tallwith an open top. Duplicate banks of 16 infrared transmitters spaced 1″apart were placed in both the X and Y directions, 1″ above the floorsurface, with aligned infrared detectors on the opposing sides of thechamber. A third bank of infrared transmitters and detectors was locatedin the X direction, 7 cm above the floor surface such that the rats usedfor these studies was required to rear on its hind limbs in order tointerrupt these beams. Each activity chamber was housed within a light-and sound-attenuating enclosure. Sessions were conducted at 16, 24, 40,48 and 72 hours post-operative and were 60 min in duration. Measurescollected include total distance traveled, total beam breaks in both theX and Y direction (ambulatory counts), repeated beam breaks within 3 cmof the animal in the absence of locomotion (stereotypy), total beambreaks in the upper X direction (rearing), time spent in ambulation,time spent in stereotypy, time spent rearing and time spent at rest. Allmeasures were collected in 6 min bins throughout the session as well assummed for the entirety of the session.

Measurement of return of aesthesia using pin prick test. At 96 hourspost-operative, animals were lightly restrained in a clear acrylicholding chamber that allows access to the abdominal area. A slightlyblunted 20 ga needle was pushed into a region within 0.5 cm of theabdominal wound site with sufficient force to noticeably involute theabdominal tissue. The needle was kept in place for 10 seconds or untilthe animal reacted by flinching or pulling away from the needle. Eachanimal was tested 2 to 3 times at the wound site. A site at least 10 cmaway from the wound area was tested in a similar manner as a positivecontrol measure.

Data analysis. Data were analyzed using a 2-factor ANOVA for repeatedmeasures with individual behavioral indices serving as the independentmeasure and both treatment group and post-operative time as thedependent variables. Post-hoc analyses were performed usingBonferroni-Dunn t-test for multiple comparisons with the sham surgerygroup serving as control and using Fisher's Protected LSD for all pairwise comparisons.

Results (distance traveled). The effects of surgery and peri-operativetreatment with either vehicle or bupivicaine are shown for each timepoint in FIGS. 1-5. There was a significant main effect of treatmentgroup and time after surgery on distance traveled with no significantinteraction between these variables (Table 1).

TABLE 2 2-Factor ANOVA results for distance traveled (cm). Source df Sumof Squares Mean Square F-Value P-Value group 7 26500237.696 3.78575E62.2594 .0288 time 4 3.37791E7 8.44478E6 5.0401 .0006 group * time 286.07196E7 2.16856E6 1.2943 .1468 Residual 435 7.28855E8 1.67553E6Dependent: distance

Post-hoc analysis using the Bonferroni/Dunn t-test for multiplecomparisons to a control group revealed that all groups administeredbupivicaine were not significantly different from sham treatment,whereas incision animals given no treatment or vehicle treated animalsremained significantly different from sham controls throughout the study(Table 2). Post-hoc analysis of all pair wise comparisons using Fisher'sProtected LSD found that only the groups administered 5% bupivicaine or1.25% bupivicaine both at the site of the peritoneal lining and at theouter muscle were not significantly different from sham (Table 3).

TABLE 3 Fisher's Protected LSD for all pair wise comparisons, distancetraveled (cm). P- Vs. Diff. Crit. diff. Value vehicle incision 116.35748474.92594 .6304 1.25% saber 213.04748 474.92594 .3784 layered in/out 5%332.81365 474.92594 .1691 2.5% saber 343.37232 474.92594 .1560 bothin/out 1.25% 402.70898 474.92594 .0963 5% saber 514.73865 474.92594.0337 S sham 825.22848 474.92594 .0007 S incision 1.25% saber 96.69000464.48674 .6826 layered in/out 5% 216.45617 464.48674 .3602 2.5% saber227.01483 464.48674 .3373 both in/out 1.25% 286.35150 464.48674 .2263 5%saber 398.38117 464.48674 .0926 sham 708.87100 464.48674 .0029 S 1.25%saber layered in/out 5% 119.76617 464.48674 .6126 2.5% saber 130.32483464.48674 .5816 both in/out 1.25% 189.66150 464.48674 .4227 5% saber301.69117 464.48674 .2024 sham 612.18100 464.48674 .0099 S layeredin/out 5% 2.5% saber 10.55867 464.48674 .9644 both in/out 1.25% 69.89533464.48674 .7676 5% saber 181.92500 464.48674 .4418 sham 492.41483464.48674 .0378 S 2.5% saber both in/out 1.25% 59.33667 464.48674 .80195% saber 171.36633 464.48674 .4688 sham 481.85617 464.48674 .0421 S bothin/out 1.25% 5% saber 112.02967 464.48674 .6357 sham 422.51950 464.48674.0745 5% saber sham 310.48983 464.48674 .1896 S = Significantlydifferent at this level.

Ambulatory counts. The statistical results for ambulatory count data isqualitatively similar to those described for distance traveled above.The data for ambulatory counts were assessed for each individual timepoint following surgery. As with distance traveled during the session,there was a significant main effect of both treatment group and timeafter surgery on ambulatory counts, with no significant interactionbetween these variables (Table 4).

TABLE 4 2-Factor ANOVA results for ambulatory counts. Source df Sum ofSquares Mean Square F-Value P-Value group 7 5.70066E6  8.1438E5 1.9317.0631 time 4 8.44878E6  2.1122E6 5.0101 .0006 group * time 28 1.42666E75.09522E5 1.2086 .2161 Residual 435 1.83392E8 4.21591E5 Dependent:ambulatory counts

Post-hoc analysis with the Bonferroni/Dunn t-test using ambulatorycounts as the independent measure yielded similar results as the datafor distance traveled (Tables 5).

TABLE 5 Bonferroni/Dunn t-test for multiple comparisons, ambulatorycounts. P- Vs. Diff. Crit. diff. Value sham incision −354.50000325.73352 .0029 S vehicle −346.51061 333.05428 .0045 S 1.25% saber−281.00000 325.73352 .0182 layered in/out 5% −213.43333 325.73352 .07252.5% saber −207.28333 325.73352 .0811 both in/out 1.25% −174.08333325.73352 .1427 5% saber −128.61667 325.73352 .2785 S = Significantlydifferent at this level.

Analysis of all pair wise comparisons with Fisher's Protected LSD foundthat the sham group was only significantly different from the controlincision group, the vehicle-treated group and the group treated with thelowest dose of bupivicaine (1.25%) (Table 6).

TABLE 6 Fisher's Protected LSD for all pair wise comparisons, ambulatorycounts. P- Vs. Diff. Crit. diff. Value incision vehicle 7.98939238.22966 .9475 1.25% saber 73.50000 232.99321 .5356 layered in/out 5%141.06667 232.99321 .2347 2.5% saber 147.21667 232.99321 .2150 bothin/out 1.25% 180.41667 232.99321 .1288 5% saber 225.88333 232.99321.0574 sham 354.50000 232.99321 .0029 S vehicle 1.25% saber 65.51061238.22966 .5891 layered in/out 5% 133.07727 238.22966 .2729 2.5% saber139.22727 238.22966 .2513 both in/out 1.25% 172.42727 238.22966 .1556 5%saber 217.89394 238.22966 .0729 sham 346.51061 238.22966 .0045 S 1.25%saber layered in/out 5% 67.56667 232.99321 .5690 2.5% saber 73.71667232.99321 .5344 both in/out 1.25% 106.91667 232.99321 .3676 5% saber152.38333 232.99321 .1993 sham 281.00000 232.99321 .0182 S layeredin/out 5% 2.5% saber 6.15000 232.99321 .9586 both in/out 1.25% 39.35000232.99321 .7401 5% saber 84.81667 232.99321 .4747 sham 213.43333232.99321 .0725 2.5% saber both in/out 1.25% 33.20000 232.99321 .7796 5%saber 78.66667 232.99321 .5073 sham 207.28333 232.99321 .0811 bothin/out 1.25% 5% saber 45.46667 232.99321 .7015 sham 174.08333 232.99321.1427 5% saber sham 128.61667 232.99321 .2785 S = Significantlydifferent at this level.

Stereotypy Counts. There were no significant differences found betweengroups for close movements (stereotypy) but there was a significant maineffect of time after surgery and a significant interaction betweentreatment group and post-surgical time (Table 7, FIGS. 11-15). Post-hocanalysis using Bonferroni/Dunn t-test revealed that the 40 hr time pointwas significantly different from the other time points for this measure(Table 8). Exclusion of the 40 hr time point and reanalysis of theremaining data by 2-factor ANOVA revealed a marginally significanteffect of treatment group on stereotypic behavior, a significant maineffect of post-surgical time and a significant interaction betweentreatment group and time after surgery (Table 9). Post-hoc analysis byBonferrroni/Dunn revealed no significant differences between treatmentgroups, but Fisher's Protected LSD t-test found that all groups weresignificantly different from sham controls with the exception of thehighest dose of bupivicaine (5%) as well as the group treated with 1.25%bupivicaine both at the level of the peritoneal lining and at theabdominal muscle layer (Table 10).

TABLE 7 2-Factor ANOVA, stereotypy counts. Source df Sum of Squares MeanSquare F-Value P-Value group 7 8.17653E6 1.16808E6 1.2165 .2921 time 42.00711E7 5.01778E6 5.2258 .0004 group * time 28 4.64266E7 1.65809E61.7268 .0131 Residual 435 4.17686E8 9.60197E5 Dependent: stereotypycounts

TABLE 8 Bonferroni/Dunn for multiple comparisons to control, time aftersurgery. P- Vs. Diff. Crit. diff. Value 24 −95.29474 367.84078 .5031 48−44.54737 367.84078 .7542 72 300.09474 367.84078 .0354 40 415.45263367.84078 .0037 S S = Significantly different at this level.

TABLE 9 2-Factor ANOVA, excluding 40 hr time point, stereotypy counts.Source df Sum of Squares Mean Square F-Value P-Value group 7  1.2537E7 1.791E6 1.8741 .0729 time 3 9.26855E6 3.08952E6 3.2329 .0225 group *time 21 3.24302E7 1.54429E6 1.616 .0435 Residual 348 3.32568E8 9.55656E5Dependent: stereotypy counts

TABLE 10 Fisher's Protected LSD for all pair wise comparisons excluding40 hr time point, stereotypy counts. P- Vs. Diff. Crit. diff. Valueincision 1.25% saber 48.54167 392.46977 .8079 2.5% saber 70.66667392.46977 .7235 layered in/out 5% 83.68750 392.46977 .6752 vehicle122.54924 401.29041 .5485 both in/out 1.25% 144.58333 392.46977 .4692 5%saber 431.95833 392.46977 .0311 S sham 530.02083 392.46977 .0083 S 1.25%saber 2.5% saber 22.12500 392.46977 .9118 layered in/out 5% 35.14583392.46977 .8603 vehicle 74.00758 401.29041 .7170 both in/out 1.25%96.04167 392.46977 .6306 5% saber 383.41667 392.46977 .0555 sham481.47917 392.46977 .0163 S 2.5% saber layered in/out 5% 13.02083392.46977 .9480 vehicle 51.88258 401.29041 .7994 both in/out 1.25%73.91667 392.46977 .7113 5% saber 361.29167 392.46977 .0711 sham459.35417 392.46977 .0219 S layered in/out 5% vehicle 38.86174 401.29041.8491 both in/out 1.25% 60.89583 392.46977 .7604 5% saber 348.27083392.46977 .0818 sham 446.33333 392.46977 .0259 S vehicle both in/out1.25% 22.03409 401.29041 .9141 5% saber 309.40909 401.29041 .1303 sham407.47159 401.29041 .0466 S both in/out 1.25% 5% saber 287.37500392.46977 .1507 sham 385.43750 392.46977 .0542 5% saber sham 98.06250392.46977 .6234 S = Significantly different at this level.

Vertical Counts (rearing). There was a significant main effect of bothtreatment group and time after surgery on rearing, as well as asignificant interaction between these variables (Table 11). Post-hocanalysis using the Bonferroni/Dunn t-test revealed significantdifferences between the sham control and all treatment groups (Table12). The results of the Fisher's Protected LSD test yielded consistentfindings, with no significant differences found with the exception ofthe sham group with all other treatments (Table 13).

TABLE 11 2-Factor ANOVA, vertical counts. Source df Sum of Squares MeanSquare F-Value P-Value group 7 25480.85893 3640.12270 6.1118 .0001 time4 7396.90415 1849.22604 3.1049 .0154 group * time 28 30524.371451090.15612 1.8304 .0067 Residual 435 259082.15909 595.59117 Dependent:vertical counts

TABLE 12 Bonferroni/Dunn for multiple comparisons to control, verticalcounts. P- Vs. Diff. Crit. diff. Value sham 1.25% saber −25.2000012.24308 .0001 S vehicle −22.60909 12.51824 .0001 S layered in/out 5%−21.95000 12.24308 .0001 S 5% saber −20.80000 12.24308 .0001 S incision−20.63333 12.24308 .0001 S both in/out 1.25% −19.08333 12.24308 .0001 S2.5% saber −18.65000 12.24308 .0001 S S = Significantly different atthis level.

TABLE 13 Fisher's Protected LSD for all pair wise comparisons, verticalcounts. P- Vs. Diff. Crit. diff. Value 1.25% saber vehicle 2.590918.95415 .5699 layered in/out 5% 3.25000 8.75733 .4661 5% saber 4.400008.75733 .3239 incision 4.56667 8.75733 .3060 both in/out 1.25% 6.116678.75733 .1705 2.5% saber 6.55000 8.75733 .1423 sham 25.20000 8.75733.0001 S vehicle layered in/out 5% .65909 8.95415 .8850 5% saber 1.809098.95415 .6915 incision 1.97576 8.95415 .6647 both in/out 1.25% 3.525768.95415 .4394 2.5% saber 3.95909 8.95415 .3853 sham 22.60909 8.95415.0001 S layered in/out 5% 5% saber 1.15000 8.75733 .7965 incision1.31667 8.75733 .7678 both in/out 1.25% 2.86667 8.75733 .5203 2.5% saber3.30000 8.75733 .4593 sham 21.95000 8.75733 .0001 S 5% saber incision.16667 8.75733 .9702 both in/out 1.25% 1.71667 8.75733 .7002 2.5% saber2.15000 8.75733 .6297 sham 20.80000 8.75733 .0001 S incision both in/out1.25% 1.55000 8.75733 .7281 2.5% saber 1.98333 8.75733 .6565 sham20.63333 8.75733 .0001 S both in/out 1.25% 2.5% saber .43333 8.75733.9226 sham 19.08333 8.75733 .0001 S 2.5% saber sham 18.65000 8.75733.0001 S S = Significantly different at this level.

Pin prick stimulus. Animals were subjected to the pin prick stimulus atan area within 0.5 cm of the incision 96 hr after surgery. All animalsresponded to this stimulus with the exception of a single animal ingroup HH (1.25% bupivicaine administered at both the abdominal musclelayer and at the peritoneal lining). This animal responded normally tothe pin prick stimulus when it was administered at a site approximately3 cm from the site of the incision.

Results. Peri-operative treatment with the vehicle used for thesustained-release composition (the control) had no significant effect onactivity measures compared to abdominal incision with no othertreatment. There was an apparent vehicle effect on stereotypic behaviorat some of the later time points. The data consistently support asignificant analgesic effect of 5% bupivicaine in the sustained-releasecomposition that appears to be present at the later time points studied.The 5% bupivicaine controlled release composition consistently providedsubstantial analgesia and reversed the effect of abdominal incision onall behavioral measures with the exception of vertical activity. Someanalgesic effects were found following administration of 1.25%bupivicaine at both the level of the peritoneal lining and at the outerabdominal muscle layer, however the effects were not as consistent asthose found following administration of 5% bupivicaine at the outermuscle layer only. The effect of 5% bupivicaine is more robust at the 48and 72 hour time points. The reason(s) for these animals displaying lessactivity at the earlier time points is(are) not readily apparent asthese animals displayed normal feeding and grooming behavior in theirhome cages and did not appear to be in distress. These data establishthat local anesthetic effect sufficient to control pain followingsurgery using the controlled release compositions of the inventioncontaining a bupivicaine anesthetic.

Example 3

The following dose escalation, safety and pharmacokinetic evaluation wascarried out in healthy human volunteer subjects in order to assess thesafety/tolerability and preliminary pharmacokinetic performance ofcontrolled release bupivacaine compositions comprising a sucrose acetateisobutyrate non-polymeric carrier.

The compositions were formulated using bupivacaine free base formulatedin a sucrose acetate isobutyrate (SAIB) non-polymeric carrier furtherincluding N-methyl-2-pyrrolidone (NMP) that acts as a solvent for thebupivacaine and the SAIB carrier. The composition was prepared bycombining the SAIB carrier and NMP solvent (70:30 vehicle) with 5 wt %of bupivacaine, to provide individual dosages containing 137.5 mg of thebupivacaine in a 2.5 mL injection volume. The composition was providedas an injectable liquid.

There were two Cohorts in the study. Cohort 1 was comprised of 6 healthymale subjects, aged from 22 to 38. For Cohort 1, all subjects received2.5 mL total volume injections of the SAIB/NMP/bupivacaine composition(containing 137.5 mg bupivacaine) at a first administration site,administered into the abdominal subcutaneous space as a 5 cm trailinginjection; and 2.5 mL placebo injections containing vehicle (SAIB/NMP)only at a second administration site, also administered into theabdominal subcutaneous space as a 5 cm trailing injection. Afteradministrations, the subjects were assessed for up to eight hours tomonitor local tissue conditions at the site of administration and plasmasamples were collected. Additional plasma samples were taken on Days 1,2, 3, 4 and 28. All plasma samples were tested for bupivacaineconcentration in the blood using standard methods.

Cohort 2 was also comprised of 6 healthy male subjects, aged from 22 to38. Cohort 2 was split into two subgroups, the first subgroup (n=3)received 5 mL total volume injections of the SAIB/NMP/bupivacainecomposition (containing 275 mg bupivacaine), administered into theabdominal subcutaneous space as two 5 cm trailing injections of 2.5 mLeach. The second subgroup (n=3) received 2.5 mL total volume placeboinjections containing vehicle (SAIB/NMP) only, also administered intothe abdominal subcutaneous space as two 5 cm trailing injections of 1.25mL each. Here again, after administrations, the subjects were assessedfor up to eight hours to monitor local tissue conditions at the site ofadministration and plasma samples were collected. Additional plasmasamples were taken on Days 1, 2, 3, 4 and 28.

As a result of the study, it was found that the SAIB carrier andSAIB/NMP/bupivacaine compositions were well tolerated, where theinjections did not result in any observable redness, swelling, itching,discoloration, or any other adverse symptom at the injections site, orany unacceptable tissue reaction throughout the duration of the study.In addition, the bupivacaine pharmacokinetic evaluations showed suitableslow (extended) release of the bupivacaine active from the SAIB carrier,releasing the bupivacaine active over a period of 3 to 4 days. Thesepharmacokinetic results are presented in FIG. 1. As can be seen, theC_(max) plasma bupivacaine concentrations following Cohort 1 (84 ng/mL)and Cohort 2 (174 ng/mL) injections were well below published estimatedtoxic plasma concentration ranges (about 1 to 4 μg/mL). In addition, acomparison between the Cohort 1 and Cohort 2 curves shows that plasmabupivacaine levels increase in a substantially linear fashion with thedose escalation. Furthermore, assessment of the AUC shows that there was100% bupivacaine bioavailability.

Example 4

The following dose escalation, pharmacokinetic, pharmacodynamic(efficacy) evaluation is carried out in human patients undergoingsurgical inguinal hernia repair procedures in order to assess theefficacy and pharmaceutical performance of controlled releasebupivacaine compositions comprising a sucrose acetate isobutyratenon-polymeric carrier and prepared in accordance with the presentinvention. The study compares the efficacy of the presentSAIB/bupivacaine compositions administered subcutaneously in combinationwith a saline (placebo) or bupivacaine hydrochloride (Marcain®) woundinfiltrate, against a commercially available bupivacaine solution(Marcain®, Bupivacaine Hydrochloride BP, 5.28 mg/mL, equivalent tobupivacaine hydrochloride anhydrous 5 mg/mL) administered subcutaneouslyand as an infiltrate in open inguinal hernia repair patients.

The test composition was/is formulated using bupivacaine free baseformulated in a sucrose acetate isobutyrate (SAIB) non-polymeric carrierfurther including benzyl alcohol (BA) that acts as a solvent for thebupivacaine and the SAIB carrier. The benzyl alcohol is also ananesthetic agent. The composition was/is prepared by combining about 66wt % of the SAIB carrier, 22 wt % of the benzyl alcoholsolvent/anesthetic, and 12 wt % of bupivacaine, to provide individualdosages containing 159.5 mg bupivacaine in a 1.25 mL injection volume(319 mg in a 2.5 mL total volume). The composition was/is provided as aninjectable clear liquid.

The study is designed to include 3 Cohorts with up to 91 patients (6patients for Cohort 1; 15 patients for Cohort 2; and up to 70 patientsfor Cohort 3). In particular, Cohort 1 was comprised of 6 healthy malesubjects, aged from 23 to 52. For Cohort 1, all patients received 2.5 mLtotal volume injections of the SAIB/BA/bupivacaine composition(containing 319 mg bupivacaine), administered as two trailingsubcutaneous injections along each side of the surgical wound (0.5 mL/cmalong a suggested 5 cm total length wound incision) with 10 mL salineinfiltrated into the incision wound (including subfascial) prior towound closure. The trailing injections were administered 0.5 to 1.0 cmaway from and parallel to the incision wound margins, and were performedby advancing the needle subcutaneously, parallel to and along the lengthof the incision, injecting continuously as the needle was withdrawn.Anesthetic/analgesic effect was assessed using Time to FirstSupplemental Analgesic Medication, and Total Supplemental AnalgesicMedication Consumption (over the course of 4 days) tests. Plasmabupivacaine concentration was measured periodically throughout thecourse of the study, particularly through the first 24 hours to assessthe magnitude of early bupivacaine release from the SAIB controlledrelease composition.

The results of the Time to First Supplemental Analgesic test arereported below in Table 14.

TABLE 14 Time to First Supplemental Analgesic. Patient # Time FirstAnalgesic Taken 1 8 hours 2 1 hour 3 1 hour 4 1 hour 5 2 hours 6 3 hours(Mean) 2.6 hours

The results of the Total Supplemental Analgesic Medication Consumption(over the course of 4 days) are reported below in Table 15.

TABLE 15 Total Supplemental Analgesic Medication Consumption. Patient #Day 1 Day 2 Day 3 Day 4 1 2 5 1 1 2 4 4 3 4 3 3 1 1 1 4 10 5 3 1 5 2 1 11 6 4 1 2 3 (Mean) 4.16 2.8 1.8 1.8

As with the Example 3 study, it was again found that theSAIB/BA/bupivacaine composition was well tolerated, where the injectionsdid not result in any observable redness, swelling, itching,discoloration, or any other adverse symptom at the injections site, orany unacceptable tissue reaction throughout the duration of the study.In addition, the bupivacaine pharmacokinetic evaluations showed extendedrelease of the bupivacaine active from the SAIB carrier, releasing thebupivacaine active over a period of 4 days. The pharmacokinetic resultsare presented in FIGS. 2 and 3. As can be seen, the SAIB/BA/bupivacainecomposition released the bupivacaine active quickly (within about 1 hourof administration) without an initial burst and showed a substantiallyconstant, steady state release over at least the first 3 days oftreatment. The observed mean C_(max) was 277 ng/mL±109; the T_(max) was23 hours±21; and the C_(ss) was 191 ng/mL±13.

Cohort 2 was comprised of 15 healthy male subjects, aged from 26 to 54.Cohort 2 was split into three subgroups, the first subgroup (n=5)received 5.0 mL total volume injections of the SAIB/BA/bupivacainecomposition (containing 638 mg bupivacaine), administered as twotrailing subcutaneous injections along each side of the surgical wound(0.5 mL/cm along a suggested 5 cm total length incision wound) with 10mL saline infiltrated into the incision wound (including subfascial)prior to wound closure. The second subgroup (n=5) received 5 mL totalvolume injections of the SAIB/BA/bupivacaine composition (containing 638mg bupivacaine), administered as two trailing subcutaneous injectionsalong each side of the surgical wound (0.5 mL/cm along a suggested 5 cmtotal length incision wound) with 10 mL Marcain® (0.5% Bupivacaine-HCl)infiltrated into the incision wound (including subfascial) prior towound closure to yield a total of 688 mg bupivacaine administered perpatient. The third subgroup (n=5) received 5 mL total volume injectionsof the Marcain® (0.5% Bupivacaine-HCl) composition administered as twotrailing subcutaneous injections along each side of the surgical wound(0.5 mL/cm along a suggested 5 cm total length incision wound) alongwith 10 mL Marcain® infiltrated into the incision wound (includingsubfascial) prior to wound closure to yield a total of 75 mg bupivacaineadministered per patient.

Anesthetic/analgesic effect was assessed using Time to FirstSupplemental Analgesic Medication, “at rest” Incision Site Pain Scores,and Total Supplemental Analgesic Medication Consumption (over the courseof 4 days) tests. Plasma bupivacaine concentration was measuredperiodically throughout the course of the study, particularly throughthe first 24 hours to assess the magnitude of early bupivacaine releasefrom the SAIB controlled release composition.

The results of the Time to First Supplemental Analgesic test, and theTotal Supplemental Analgesic Medication Consumption (over the course of4 days) test for all three subgroups for Cohort 2 are reported below inTable 16.

TABLE 16 Mean Time to First Supplemental Analgesic and Mean TotalSupplemental Analgesic Medication Consumption (over the course of 4days). Mean Time to Mean Number First of Supplemental NumberSupplemental Analgesic Doses of Analgesic (in Taken Over 4 SubgroupPatients Treatment hours) Days 1 n = 5 SAIB/BA/Bupivacaine and 60.4* 2.6Saline (638 mg total dose) 2 n = 5 SAIB/BA/Bupivacaine and 44.9* 2.4Marcain ® (688 mg total dose) 3 n = 5 Marcain ® (75 mg total dose) 2.311.0 (*Three patients in Subgroup 1 and two patients in Subgroup 2 tookno supplemental analgesic doses over the entire 4 day period.)

Once again, the SAIB/BA/bupivacaine composition was well tolerated (thesubgroup 1 and 2 patients), where the injections did not result in anyobservable redness, swelling, itching, discoloration, or any otheradverse symptom at the injections site, or any unacceptable tissuereaction throughout the duration of the study. In addition, thebupivacaine pharmacokinetic evaluations showed extended release of thebupivacaine active from the SAIB carrier, releasing the bupivacaineactive over a period of 4 days. The pharmacokinetic results arepresented in FIGS. 4 and 5. As can be seen, the SAIB/BA/bupivacainecomposition released the bupivacaine active quickly (within about 1 hourof administration) without an initial burst and showed a substantiallyconstant, steady state release over at least the first 3 days oftreatment.

The pharmacodynamics for all three subgroups of Cohort 2 are reportedbelow in Table 17.

TABLE 17 Pharmacodynamics for Cohort 2. Number of Cmax Tmax Css SubgroupPatients Treatment (ng/mL) (hours) (ng/ml) 1 n = 5 SAIB/BA/Bupivacaineand  470 ± 155 21 ± 25 311 ± 58 Saline (638 mg total dose) 2 n = 5SAIB/BA/Bupivacaine and 310 ± 60 21 ± 25 291 ± 40 Marcain ® (688 mgtotal dose) 3 n = 5 Marcain ® (75 mg total dose) 180 ± 88 0.6 ± 0.2 NA

As can be seen from the results of the Cohort 2 study, the instantcontrolled release compositions provide effective local anestheticeffect over the course of at least 4 days after surgery, greatlyreducing the need for supplemental analgesic medications. In fact, 50%of the patients receiving the SAIB/BA/Bupivacaine compositions of thepresent invention (5 out of 10 patients in subgroups 1 and 2) requiredno supplemental pain medications over the entire 4 day period. Thosepatients in subgroups 1 and 2 that did require supplemental analgesicmedications were still able to await their first additional painmedications for about 2-3 days, showing effective local anestheticeffect over the course of at least 2 days after surgery. In addition,the amount of doses of supplemental analgesic medications in subgroups 1and 2 were drastically reduced relative to the control (subgroup 3)patients who required on average 11 doses over the 4 day test period ascontrasted with 2.4 to 2.6 doses over the same period.

Furthermore, a review of the pharmacokinetic data from Cohort 2 suggeststhat an efficacious subcutaneous dose of 638-688 mg bupivacaine can bereproducibly administered using the controlled release compositions ofthe present invention to provide an efficacious steady state plasmaconcentration of bupivacaine of about 300 ng/mL.

The results of the “at rest” Incision Site Pain Scores test for allthree subgroups of Cohort 2 are depicted in FIG. 6. The subgroup 3 datais represented by the top curve (?), the subgroup 2 data is representedby the middle curve (?), and the subgroup 1 data is represented by thebottom curve (?). For convenience, the average time to firstsupplemental analgesic is shown on each curve. The incision painintensity was recorded using a 0 to 100 mm visual analog scale (VAS)with scores ranging from 0 (no pain) to 100 (worst pain imaginable).Each VAS score was recorded as a single vertical line on the scale. Thetest was administered as follows. On the day of surgery (Day 0),incision pain scores were recorded initially at 60 minutes afteradministration of the test composition (as discussed above, subgroup 1received SAIB/BA/bupivacaine and saline; subgroup 2 receivedSAIB/BA/bupivacaine and Marcain®; and subgroup 3 received Marcain® andMarcain®). Thereafter, incision pain scores were recorded every 30minutes through the 4 hour evaluation time point, and then hourlythrough the 8 hour evaluation time point, and finally at the 12 hourevaluation time point. On follow-on Days 1 through 3, incision painscores were recorded in the morning based upon the time that the testcomposition was administered on Day 0. These follow-on measurements weretaken at 4-hour intervals through a 12 hour evaluation period (4measurements). The time of use of any concomitant (supplemental)medications was also noted during this 4-day evaluation.

As can be seen by reviewing the results of the Incision Site Pain Scorestest depicted in FIG. 6, both subgroups that received theSAIB/BA/bupivacaine test compositions (subgroups 1 and 2) displayedlower mean VAS scores at all times throughout the test as compared withthe group that received the Marcain® test composition (subgroup 3).These results demonstrate that the compositions of the present inventionprovide sustained local anesthesia at the incision wound site with aduration of at least about 36 to 48 hours after administration to thesubject.

Patients for Cohort 3 will be divided into 2 treatment subgroups. Thefirst subgroup will receive 7.5 mL total volume injections of theSAIB/BA/bupivacaine composition (containing 958 mg bupivacaine),administered as two trailing subcutaneous injections along each side ofthe surgical wound (0.75 mL/cm along a suggested 5 cm total lengthincision wound) with 10 mL Marcain® (0.5% Bupivacaine-HCl) infiltratedinto the incision wound (including subfascial) prior to wound closure toyield a total of 1,008 mg bupivacaine administered per patient. Thesecond subgroup will receive 7.5 mL total volume injections of theMarcain® (0.5% Bupivacaine-HCl) composition administered as two trailingsubcutaneous injections along each side of the surgical wound (0.75mL/cm along a suggested 5 cm total length incision wound) along with 10mL Marcain® infiltrated into the incision wound (including subfascial)prior to wound closure to yield a total of 87.5 mg bupivacaineadministered per patient.

Anesthetic/analgesic effect will be assessed using Time to FirstSupplemental Analgesic Medication, and Total Supplemental AnalgesicMedication Consumption (over the course of 4 days) tests. Plasmabupivacaine concentration will be measured periodically throughout thecourse of the study, particularly through the first 24 hours to assessthe magnitude of early bupivacaine release from the SAIB controlledrelease composition. It is expected that the higher doseSAIB/BA/Bupivacaine controlled release compositions prepared accordingto the present invention will provide similar or even greater efficacyresults as compared with those of the Cohort 2 test subjects.

The present invention having been thus described, variations andmodifications thereof as would be apparent to those of skill in the artwill be understood to be within the scope of the appended claims.

1.-181. (canceled)
 182. A method for providing an anesthetic effect at awound in a subject, comprising administering a controlled deliverycomposition into the wound, wherein the controlled delivery compositioncomprises bupivacaine, and further wherein the administering provides asustained local anesthetic effect at the wound having a duration of atleast 48 hours after the administration.
 183. The method of claim 182,wherein the sustained local anesthetic effect is for at least 72 hoursafter the administration.
 184. The method of claim 182, wherein thesustained local anesthetic effect is for up to 4 days after theadministration.
 185. The method of claim 182, wherein the bupivacaine ispresent in the controlled delivery composition in an amount ranging from1 wt % to 10 wt %, based on weight of the controlled deliverycomposition.
 186. The method of claim 182, wherein the bupivacaine ispresent in the controlled delivery composition in an amount ranging from1 wt % to 5 wt %, based on weight of the controlled deliverycomposition.
 187. The method of claim 182, wherein the bupivacaine ispresent in the controlled delivery composition in an amount ranging from2 wt % to 5 wt %, based on weight of the controlled deliverycomposition.
 188. The method of claim 182, wherein the bupivacaine ispresent in free base form.
 189. The method of claim 182, wherein thecontrolled delivery composition comprises a polymer.
 190. The method ofclaim 189, wherein the polymer comprises a polyorthoester.
 191. Themethod of claim 182, wherein the controlled delivery compositioncomprises an organic solvent.
 192. The method of claim 191, wherein theorganic solvent comprises dimethyl sulfoxide and glyceryl triacetate.193. The method of claim 191, wherein the organic solvent is present inthe controlled delivery composition in an amount ranging from 10 wt % to55 wt %, based on weight of the controlled delivery composition. 194.The method of claim 191, wherein the organic solvent is present in thecontrolled delivery composition in an amount ranging from 15 wt % to 50wt %, based on weight of the controlled delivery composition.
 195. Themethod of claim 191, wherein the organic solvent is present in thecontrolled delivery composition in an amount ranging from 25 wt % to 55wt %, based on weight of the controlled delivery composition.
 196. Themethod of claim 191, wherein the organic solvent is present in thecontrolled delivery composition in an amount ranging from 25 wt % to 50wt %, based on weight of the controlled delivery composition.
 197. Themethod of claim 182, wherein the wound is a surgical wound.
 198. Themethod of claim 182, wherein the bupivacaine is present in thecontrolled delivery composition in an amount ranging from 2 wt % to 5 wt%, based on weight of the controlled delivery composition; and thecontrolled delivery composition comprises an organic solvent present inthe controlled delivery composition in an amount ranging from 25 wt % to50 wt %, based on weight of the controlled delivery composition. 199.The method of claim 182, wherein the bupivacaine is present in thecontrolled delivery composition in an amount ranging from 2 wt % to 5 wt%, based on weight of the controlled delivery composition; and thecontrolled delivery composition comprises a polymer comprising apolyorthoester.
 200. The method of claim 182, wherein the bupivacaine ispresent in the controlled delivery composition in an amount ranging from2 wt % to 5 wt %, based on weight of the controlled deliverycomposition; the controlled delivery composition comprises a polymercomprising a polyorthoester; and the controlled delivery compositioncomprises an organic solvent present in the controlled deliverycomposition in an amount ranging from 25 wt % to 50 wt %, based onweight of the controlled delivery composition.
 201. The method of claim182, wherein the bupivacaine is present in the controlled deliverycomposition in an amount ranging from 2 wt % to 5 wt %, based on weightof the controlled delivery composition; the controlled deliverycomposition comprises a polymer comprising a polyorthoester; thecontrolled delivery composition comprises an organic solvent present inthe controlled delivery composition in an amount ranging from 25 wt % to50 wt %, based on weight of the controlled delivery composition; and thewound is a surgical wound.
 202. The method of claim 182, wherein thebupivacaine is present in the controlled delivery composition in anamount ranging from 2 wt % to 5 wt %, based on weight of the controlleddelivery composition; the bupivacaine is present in free base form; thecontrolled delivery composition comprises a polymer comprising apolyorthoester; the controlled delivery composition comprises an organicsolvent present in the controlled delivery composition in an amountranging from 25 wt % to 50 wt %, based on weight of the controlleddelivery composition; and the wound is a surgical wound.
 203. The methodof claim 182, wherein the bupivacaine is present in the controlleddelivery composition in an amount ranging from 2 wt % to 5 wt %, basedon weight of the controlled delivery composition; the controlleddelivery composition comprises an organic solvent present in thecontrolled delivery composition in an amount ranging from 25 wt % to 50wt %, based on weight of the controlled delivery composition; and theorganic solvent comprises dimethyl sulfoxide and glyceryl triacetate.204. The method of claim 182, wherein the bupivacaine is present in thecontrolled delivery composition in an amount ranging from 2 wt % to 5 wt%, based on weight of the controlled delivery composition; thecontrolled delivery composition comprises a polymer comprising apolyorthoester; the controlled delivery composition comprises an organicsolvent present in the controlled delivery composition in an amountranging from 25 wt % to 50 wt %, based on weight of the controlleddelivery composition; and the organic solvent comprises dimethylsulfoxide and glyceryl triacetate.
 205. The method of claim 182, whereinthe bupivacaine is present in the controlled delivery composition in anamount ranging from 2 wt % to 5 wt %, based on weight of the controlleddelivery composition; the controlled delivery composition comprises apolymer comprising a polyorthoester; the controlled delivery compositioncomprises an organic solvent present in the controlled deliverycomposition in an amount ranging from 25 wt % to 50 wt %, based onweight of the controlled delivery composition; the organic solventcomprises dimethyl sulfoxide and glyceryl triacetate; and the wound is asurgical wound.
 206. The method of claim 182, wherein the bupivacaine ispresent in the controlled delivery composition in an amount ranging from2 wt % to 5 wt %, based on weight of the controlled deliverycomposition; the bupivacaine is present in free base form; thecontrolled delivery composition comprises a polymer comprising apolyorthoester; the controlled delivery composition comprises an organicsolvent present in the controlled delivery composition in an amountranging from 25 wt % to 50 wt %, based on weight of the controlleddelivery composition; the organic solvent comprises dimethyl sulfoxideand glyceryl triacetate; and the wound is a surgical wound.